Director, NIH Center of Excellence in Genomic Science at Stanford: The Genomic Basis of Vertebrate Diversity (2007 - 2012)
Honors & Awards
Scholar in Biomedical Research, Lucille P. Markey Foundation (1989 to 1996)
Researcher, Howard Hughes Medical Institute (1997 to present)
Fellow, American Academy of Arts and Sciences (2005)
Conklin Medal, Society for Developmental Biology (2009)
Member, National Academy of Sciences (2011)
Ph.D., MIT, Biology (1986)
B.S., Yale, Biology (1981)
Community and International Work
Stickleback Genome Project and Summer Training Course, Stanford
NIH Human Genome Research Institute
Worldwide research community in vertebrate genetics
Opportunities for Student Involvement
Current Research and Scholarly Interests
Naturally occurring species show spectacular differences in morphology, physiology, lifestyle, and behavior. They also differ in disease susceptibility and life span. Although the genomes of many organisms have now been completely sequenced, we still know relatively little about the specific DNA sequence changes that underlie interesting species-specific traits. My laboratory is using a combination of genetic and genomic approaches to identify the detailed molecular mechanisms that control evolutionary change in vertebrates, with a focus on five fundamental questions:
1. Are new evolutionary traits controlled by countless genetic differences of small effect, or by a few genetic changes with large effects?
2. What specific genes have changed to produce interesting evolutionary differences seen in nature?
3. What kinds of mutations have occurred in these genes (e.g., dominant or recessive, coding or regulatory, preexisting or de novo)?
4. How predictable is evolution? If you know how evolution has occurred in one population, is it possible to predict the genes and mutations that also underlie the same trait in different populations?
5. How has evolution produced the unique characteristics of humans?
We study these questions using a variety of methods in mice, sticklebacks, and people.
Mice are often the best system available for asking detailed mechanistic questions in mammals, or testing the phenotypic effects of particular sequence changes seen in other species. We have used classical genetics in mice to identify fundamental pathways that control formation and patterning of cartilage, bone, and joints. We also make extensive use of mice identifying the regulatory mechanisms that lay out expression of key developmental control genes, with the ultimate aim of identifying how vertebrate morphology itself is encoded in the genome.
Sticklebacks offer an unusually powerful system for studying the molecular basis of evolutionary change in naturally occurring species. Our lab has pioneered the development of a large number of new genetic and genomic resources for the fish, and has worked with Hudson Alpha Institute and the Broad Institute to develop a mapped, whole genome sequence assembly for sticklebacks. Using these new tools, we have now successfully identified both the molecular mechanisms that control repeated evolution of armor plate patterning, pelvic reduction, and skin color changes in nature. Our studies show that big evolutionary changes can be controlled by single chromosome regions. The big changes are controlled by alterations in major developmental control genes (key signaling molecules and transcription factors). Although null mutations in these genes are typically deleterious or lethal, sticklebacks have made regulatory alterations in these genes that produce large morphological effects in particular tissues, while preserving overall viability. Interestingly, the same genes are used repeatedly when similar phenotypes evolve in different populations, revealing a surprising commonality to the molecular mechanisms that control rapid evolutionary change in diverse organisms.
Although many of our studies have begun in mice or sticklebacks, the genes and mechanisms that we have also turn out to control major differences in human morphology, human arthritis and cancer incidence, and differences in skin color in billions of people around the world. Building on this work, we have now begun a variety of projects to identify other mechanisms responsible for interesting evolutionary traits in humans. Although we are still far from knowing the detailed molecular basis of most human traits, we are optimistic that many aspects of this problem can now be studied both computationally and experimentally, and will provide new insights into how humans have evolved and adapted to many environments around the world.
- Development and Disease Mechanisms
DBIO 201 (Aut)
- Genetics and Developmental Biology Training Camp
DBIO 200, GENE 200 (Aut)
Independent Studies (7)
- Directed Reading in Developmental Biology
DBIO 299 (Aut, Win, Spr)
- Directed Reading in Neurosciences
NEPR 299 (Aut, Win, Spr)
- Graduate Research
DBIO 399 (Aut, Win, Spr)
- Graduate Research
NEPR 399 (Aut, Win, Spr)
- Medical Scholars Research
DBIO 370 (Aut, Win, Spr)
- Out-of-Department Advanced Research Laboratory in Experimental Biology
BIO 199X (Sum)
- Undergraduate Research
DBIO 199 (Aut, Win, Spr)
- Directed Reading in Developmental Biology
Prior Year Courses
- Development and Disease Mechanisms
DBIO 201 (Aut)
- Genetics and Developmental Biology Training Camp
DBIO 200, GENE 200 (Aut)
- Development and Disease Mechanisms
DBIO 201 (Aut)
- Genetics and Developmental Biology Training Camp
GENE 200 (Aut)
- Development and Disease Mechanisms
The genomic basis of adaptive evolution in threespine sticklebacks.
2012; 484 (7392): 55-61
Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature.
View details for DOI 10.1038/nature10944
View details for PubMedID 22481358
Human-specific loss of regulatory DNA and the evolution of human-specific traits
2011; 471 (7337): 216-219
Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown. Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species. Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor (AR) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionary divergence.
View details for DOI 10.1038/nature09774
View details for Web of Science ID 000288170200037
View details for PubMedID 21390129
Adaptive Evolution of Pelvic Reduction in Sticklebacks by Recurrent Deletion of a Pitx1 Enhancer
2010; 327 (5963): 302-305
The molecular mechanisms underlying major phenotypic changes that have evolved repeatedly in nature are generally unknown. Pelvic loss in different natural populations of threespine stickleback fish has occurred through regulatory mutations deleting a tissue-specific enhancer of the Pituitary homeobox transcription factor 1 (Pitx1) gene. The high prevalence of deletion mutations at Pitx1 may be influenced by inherent structural features of the locus. Although Pitx1 null mutations are lethal in laboratory animals, Pitx1 regulatory mutations show molecular signatures of positive selection in pelvic-reduced populations. These studies illustrate how major expression and morphological changes can arise from single mutational leaps in natural populations, producing new adaptive alleles via recurrent regulatory alterations in a key developmental control gene.
View details for DOI 10.1126/science.1182213
View details for Web of Science ID 000273629700034
View details for PubMedID 20007865
Shaping Skeletal Growth by Modular Regulatory Elements in the Bmp5 Gene
2008; 4 (12)
Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body.
View details for DOI 10.1371/journal.pgen.1000308
View details for Web of Science ID 000263667900023
View details for PubMedID 19096511
Role of the mouse ank gene in control of tissue calcification and arthritis
2000; 289 (5477): 265-270
Mutation at the mouse progressive ankylosis (ank) locus causes a generalized, progressive form of arthritis accompanied by mineral deposition, formation of bony outgrowths, and joint destruction. Here, we show that the ank locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. A highly conserved gene is present in humans and other vertebrates. These results identify ANK-mediated control of pyrophosphate levels as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals.
View details for Web of Science ID 000088169400033
View details for PubMedID 10894769
A "Forward Genomics'' Approach Links Genotype to Phenotype using Independent Phenotypic Losses among Related Species
2012; 2 (4): 817-823
Genotype-phenotype mapping is hampered by countless genomic changes between species. We introduce a computational "forward genomics" strategy that-given only an independently lost phenotype and whole genomes-matches genomic and phenotypic loss patterns to associate specific genomic regions with this phenotype. We conducted genome-wide screens for two metabolic phenotypes. First, our approach correctly matches the inactivated Gulo gene exactly with the species that lost the ability to synthesize vitamin C. Second, we attribute naturally low biliary phospholipid levels in guinea pigs and horses to the inactivated phospholipid transporter Abcb4. Human ABCB4 mutations also result in low phospholipid levels but lead to severe liver disease, suggesting compensatory mechanisms in guinea pig and horse. Our simulation studies, counts of independent changes in existing phenotype surveys, and the forthcoming availability of many new genomes all suggest that forward genomics can be applied to many phenotypes, including those relevant for human evolution and disease.
View details for DOI 10.1016/j.celrep.2012.08.032
View details for Web of Science ID 000314455600014
View details for PubMedID 23022484
GENETIC SIGNATURE OF ADAPTIVE PEAK SHIFT IN THREESPINE STICKLEBACK
2012; 66 (8): 2439-2450
Transition of an evolving population to a new adaptive optimum is predicted to leave a signature in the distribution of effect sizes of fixed mutations. If they affect many traits (are pleiotropic), large effect mutations should contribute more when a population evolves to a farther adaptive peak than to a nearer peak. We tested this prediction in wild threespine stickleback fish (Gasterosteus aculeatus) by comparing the estimated frequency of large effect genetic changes underlying evolution as the same ancestor adapted to two lake types since the end of the ice age. A higher frequency of large effect genetic changes (quantitative trait loci) contributed to adaptive evolution in populations that adapted to lakes representing a more distant optimum than to lakes in which the optimum phenotype was nearer to the ancestral state. Our results also indicate that pleiotropy, not just optimum overshoot, contributes to this difference. These results suggest that a series of adaptive improvements to a new environment leaves a detectable mark in the genome of wild populations. Although not all assumptions of the theory are likely met in natural systems, the prediction may be robust enough to the complexities of natural environments to be useful when forecasting adaptive responses to large environmental changes.
View details for DOI 10.1111/j.1558-5646.2012.01622.x
View details for Web of Science ID 000306804100008
View details for PubMedID 22834743
A Genome-wide SNP Genotyping Array Reveals Patterns of Global and Repeated Species-Pair Divergence in Sticklebacks
2012; 22 (1): 83-90
Genes underlying repeated adaptive evolution in natural populations are still largely unknown. Stickleback fish (Gasterosteus aculeatus) have undergone a recent dramatic evolutionary radiation, generating numerous examples of marine-freshwater species pairs and a small number of benthic-limnetic species pairs found within single lakes . We have developed a new genome-wide SNP genotyping array to study patterns of genetic variation in sticklebacks over a wide geographic range, and to scan the genome for regions that contribute to repeated evolution of marine-freshwater or benthic-limnetic species pairs. Surveying 34 global populations with 1,159 informative markers revealed substantial genetic variation, with predominant patterns reflecting demographic history and geographic structure. After correcting for geographic structure and filtering for neutral markers, we detected large repeated shifts in allele frequency at some loci, identifying both known and novel loci likely contributing to marine-freshwater and benthic-limnetic divergence. Several novel loci fall close to genes implicated in epithelial barrier or immune functions, which have likely changed as sticklebacks adapt to contrasting environments. Specific alleles differentiating sympatric benthic-limnetic species pairs are shared in nearby solitary populations, suggesting an allopatric origin for adaptive variants and selection pressures unrelated to sympatry in the initial formation of these classic vertebrate species pairs.
View details for DOI 10.1016/j.cub.2011.11.045
View details for Web of Science ID 000299144200027
View details for PubMedID 22197244
- From Atoms to Traits SCIENTIFIC AMERICAN 2009; 300 (1): 52-59
Dual hindlimb control elements in the Tbx4 gene and region-specific control of bone size in vertebrate limbs
2008; 135 (15): 2543-2553
The Tbx4 transcription factor is crucial for normal hindlimb and vascular development, yet little is known about how its highly conserved expression patterns are generated. We have used comparative genomics and functional scanning in transgenic mice to identify a dispersed group of enhancers controlling Tbx4 expression in different tissues. Two independent enhancers control hindlimb expression, one located upstream and one downstream of the Tbx4 coding exons. These two enhancers, hindlimb enhancer A and hindlimb enhancer B (HLEA and HLEB), differ in their primary sequence, in their precise patterns of activity within the hindlimb, and in their degree of sequence conservation across animals. HLEB is highly conserved from fish to mammals. Although Tbx4 expression and hindlimb development occur at different axial levels in fish and mammals, HLEB cloned from either fish or mouse is capable of driving expression at the appropriate position of hindlimb development in mouse embryos. HLEA is highly conserved only in mammals. Deletion of HLEA from the endogenous mouse locus reduces expression of Tbx4 in the hindlimb during embryogenesis, bypasses the embryonic lethality of Tbx4-null mutations, and produces viable, fertile mice with characteristic changes in the size of bones in the hindlimb but not the forelimb. We speculate that dual hindlimb enhancers provide a flexible genomic mechanism for altering the strength and location of Tbx4 expression during normal development, making it possible to separately modify the size of forelimb and hindlimb bones during vertebrate evolution.
View details for DOI 10.1242/dev.017384
View details for Web of Science ID 000257557200006
View details for PubMedID 18579682
Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation
BMC DEVELOPMENTAL BIOLOGY
Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. Although the processes of mechanotransduction and functional response of bone to mechanical strain have been extensively studied, the molecular signaling mechanisms that mediate the response of bone cells to mechanical stimulation remain unclear.Here, we identify a novel germline mutation at the mouse Bone morphogenetic protein 5 (Bmp5) locus. Genetic analysis shows that the mutation occurs at a site encoding the proteolytic processing sequence of the BMP5 protein and blocks proper processing of BMP5. Anatomic studies reveal that this mutation affects the formation of multiple skeletal features including several muscle-induced skeletal sites in vivo. Biomechanical studies of osteoblasts from these anatomic sites show that the mutation inhibits the proper response of bone cells to mechanical stimulation.The results from these genetic, biochemical, and biomechanical studies suggest that BMPs are required not only for skeletal patterning during embryonic development, but also for bone response and remodeling to mechanical stimulation at specific anatomic sites in the skeleton.
View details for DOI 10.1186/1471-213X-8-35
View details for Web of Science ID 000255931900001
View details for PubMedID 18380899
cis-regulatory changes in kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans
2007; 131 (6): 1179-1189
Dramatic pigmentation changes have evolved within most vertebrate groups, including fish and humans. Here we use genetic crosses in sticklebacks to investigate the parallel origin of pigmentation changes in natural populations. High-resolution mapping and expression experiments show that light gills and light ventrums map to a divergent regulatory allele of the Kit ligand (Kitlg) gene. The divergent allele reduces expression in gill and skin tissue and is shared by multiple derived freshwater populations with reduced pigmentation. In humans, Europeans and East Asians also share derived alleles at the KITLG locus. Strong signatures of selection map to regulatory regions surrounding the gene, and admixture mapping shows that the KITLG genomic region has a significant effect on human skin color. These experiments suggest that regulatory changes in Kitlg contribute to natural variation in vertebrate pigmentation, and that similar genetic mechanisms may underlie rapid evolutionary change in fish and humans.
View details for DOI 10.1016/j.cell.2007.10.055
View details for Web of Science ID 000252217100024
View details for PubMedID 18083106
Constraints on utilization of the EDA-signaling pathway in threespine stickleback evolution
EVOLUTION & DEVELOPMENT
2007; 9 (2): 141-154
Many traits evolve in parallel in widely separated populations. The evolutionary radiation of threespine sticklebacks provides a powerful model for testing the molecular basis of parallel evolution in vertebrates. Although marine sticklebacks are completely covered with bony armor plates, most freshwater populations have dramatic reductions in plates. Recent genetic studies have shown that major changes in armor patterning are likely due to regulatory alterations in the gene encoding the secreted signaling molecule ectodysplasin (EDA). In mammals, mutations in many different components of the EDA-signaling pathway produce similar changes in hair, teeth, sweat glands, and dermal bones. To test whether other genes in the EDA pathway also control natural variation in armor plates, we identified and mapped stickleback EDA Receptor (EDAR), the EDAR-Associated Death Domain adaptor, Tumor Necrosis Factor Receptor (TNFR) SuperFamily member 19, its adaptor TNFR-Associated Factor 6, and the downstream regulator nuclear factor kappa B Essential Modulator (NEMO). In contrast to the diversity of genes underlying ectodermal dysplasia disease phenotypes in humans, none of these EDA pathway components map to chromosomes previously shown to modify armor plates in natural populations, though EDAR showed a small but significant effect on plate number. We further investigated whether these genes exhibit differences in copy number, target size, or genomic organization that might make them less suitable targets for evolutionary change. In comparison with EDA, all these genes have smaller surrounding noncoding (putative regulatory) regions, with fewer evolutionarily conserved regions. We suggest that the presence of highly modular cis-acting control sequences may be a key factor influencing the likelihood that particular genes will serve as the basis of major phenotypic changes in nature.
View details for Web of Science ID 000244942700004
View details for PubMedID 17371397
Biochemical and genetic analysis of ANK in arthritis and bone disease
AMERICAN JOURNAL OF HUMAN GENETICS
2006; 79 (6): 1017-1029
Mutations in the progressive ankylosis gene (Ank/ANKH) cause surprisingly different skeletal phenotypes in mice and humans. In mice, recessive loss-of-function mutations cause arthritis, ectopic crystal formation, and joint fusion throughout the body. In humans, some dominant mutations cause chondrocalcinosis, an adult-onset disease characterized by the deposition of ectopic joint crystals. Other dominant mutations cause craniometaphyseal dysplasia, a childhood disease characterized by sclerosis of the skull and abnormal modeling of the long bones, with little or no joint pathology. Ank encodes a multiple-pass transmembrane protein that regulates pyrophosphate levels inside and outside tissue culture cells in vitro, but its mechanism of action is not yet clear, and conflicting models have been proposed to explain the effects of the human mutations. Here, we test wild-type and mutant forms of ANK for radiolabeled pyrophosphate-transport activity in frog oocytes. We also reconstruct two human mutations in a bacterial artificial chromosome and test them in transgenic mice for rescue of the Ank null phenotype and for induction of new skeletal phenotypes. Wild-type ANK stimulates saturable transport of pyrophosphate ions across the plasma membrane, with half maximal rates attained at physiological levels of pyrophosphate. Chondrocalcinosis mutations retain apparently wild-type transport activity and can rescue the joint-fusion phenotype of Ank null mice. Craniometaphyseal dysplasia mutations do not transport pyrophosphate and cannot rescue the defects of Ank null mice. Furthermore, microcomputed tomography revealed previously unappreciated phenotypes in Ank null mice that are reminiscent of craniometaphyseal dysplasia. The combination of biochemical and genetic analyses presented here provides insight into how mutations in ANKH cause human skeletal disease.
View details for Web of Science ID 000242131600003
View details for PubMedID 17186460
Parallel genetic origins of pelvic reduction in vertebrates
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (37): 13753-13758
Despite longstanding interest in parallel evolution, little is known about the genes that control similar traits in different lineages of vertebrates. Pelvic reduction in stickleback fish (family Gasterosteidae) provides a striking example of parallel evolution in a genetically tractable system. Previous studies suggest that cis-acting regulatory changes at the Pitx1 locus control pelvic reduction in a population of threespine sticklebacks (Gasterosteus aculeatus). In this study, progeny from intergeneric crosses between pelvic-reduced threespine and ninespine (Pungitius pungitius) sticklebacks also showed severe pelvic reduction, implicating a similar genetic origin for this trait in both genera. Comparative sequencing studies in complete and pelvic-reduced Pungitius revealed no differences in the Pitx1 coding sequences, but Pitx1 expression was absent from the prospective pelvic region of larvae from pelvic-reduced parents. A much more phylogenetically distant example of pelvic reduction, loss of hindlimbs in manatees, shows a similar left-right size bias that is a morphological signature of Pitx1-mediated pelvic reduction in both sticklebacks and mice. These multiple lines of evidence suggest that changes in Pitx1 may represent a key mechanism of morphological evolution in multiple populations, species, and genera of sticklebacks, as well as in distantly related vertebrate lineages.
View details for DOI 10.1073/pnas.0604706103
View details for Web of Science ID 000240648300038
View details for PubMedID 16945911
Mineral formation in joints caused by complete or joint-specific loss of ANK function
JOURNAL OF BONE AND MINERAL RESEARCH
2006; 21 (8): 1238-1247
To reveal the ANK complete loss of function phenotype in mice, we generated conditional and null alleles. Mice homozygous for the null allele exhibited widespread joint mineralization, similar in severity to animals harboring the original ank allele. A delayed yet similar phenotype was observed in mice with joint-specific loss of ANK function.The ANK pyrophosphate regulator was originally identified and proposed to play a key role in articular cartilage maintenance based on a single spontaneous mouse mutation (ank) that causes severe generalized arthritis. A number of human mutations have subsequently been reported in the human ortholog (ANKH), some of which produce skull and long bone defects with no apparent defects in joints or articular cartilage. None of the currently known mouse or human mutations clearly eliminate the function of the endogenous gene.Two new Ank alleles were generated using homologous recombination in mouse embryonic stem (ES) cells. Joint range of motion assays and muCT studies were used to quantitatively assess phenotypic severity in wildtype, heterozygous, and homozygous mice carrying either the null (Anknull) or original (Ankank) allele. A Gdf5-Cre expressing line was crossed to mice harboring the conditional (Ankfloxp) allele to eliminate ANK function specifically in the joints. Histological stains and beta-galactosidase (LACZ) activity were used to determine the correlation between local loss of ANK function and defective joint phenotypes.Anknull/Anknull mice develop severe ectopic postnatal crystal deposition in almost every joint of the body, leading to eventual joint fusion and loss of mobility. The severity of phenotype in these mice is indistinguishable from that of Ankank/Ankank mice. In addition, despite the widespread expression of Ank in many tissues, the specific deletion of Ank in joints also produces joint mineralization and ankylosis.These studies show that ANK function is required locally in joints to inhibit mineral formation and that the Ank gene plays a key role in postnatal maintenance of joint mobility and function.
View details for DOI 10.1359/JBMR.060515
View details for Web of Science ID 000239299400008
View details for PubMedID 16869722
Widespread parallel evolution in sticklebacks by repeated fixation of ectodysplasin alleles
2005; 307 (5717): 1928-1933
Major phenotypic changes evolve in parallel in nature by molecular mechanisms that are largely unknown. Here, we use positional cloning methods to identify the major chromosome locus controlling armor plate patterning in wild threespine sticklebacks. Mapping, sequencing, and transgenic studies show that the Ectodysplasin (EDA) signaling pathway plays a key role in evolutionary change in natural populations and that parallel evolution of stickleback low-plated phenotypes at most freshwater locations around the world has occurred by repeated selection of Eda alleles derived from an ancestral low-plated haplotype that first appeared more than two million years ago. Members of this clade of low-plated alleles are present at low frequencies in marine fish, which suggests that standing genetic variation can provide a molecular basis for rapid, parallel evolution of dramatic phenotypic change in nature.
View details for DOI 10.1126/science.1107239
View details for Web of Science ID 000227957300048
View details for PubMedID 15790847
BMP receptor signaling is required for postnatal maintenance of articular cartilage
2004; 2 (11): 1815-1827
Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.
View details for DOI 10.1371/journal.pbio.0020355
View details for Web of Science ID 000225160300013
View details for PubMedID 15492776
The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome
2004; 14 (16): 1416-1424
Many different environmental and genetic sex-determination mechanisms are found in nature. Closely related species can use different master sex-determination switches, suggesting that these developmental pathways can evolve very rapidly. Previous cytological studies suggest that recently diverged species of stickleback fish have different sex chromosome complements. Here, we investigate the genetic and chromosomal mechanisms that underlie sex determination in the threespine stickleback (Gasterosteus aculeatus).Genome-wide linkage mapping identifies a single chromosome region at the distal end of linkage group (LG) 19, which controls male or female sexual development in threespine sticklebacks. Although sex chromosomes are not cytogenetically visible in this species, several lines of evidence suggest that LG 19 is an evolving sex chromosome system, similar to the XX female/XY male system in many other species: (1) males are consistently heterozygous for unique alleles in this region; (2) recombination between loci linked to the sex-determination region is reduced in male meiosis relative to female meiosis; (3) sequence analysis of X- and Y-specific bacterial artificial chromosome (BAC) clones from the sex-determination region reveals many sequence differences between the X- and Y-specific clones; and (4) the Y chromosome has accumulated transposable elements and local duplications.Taken together, our data suggest that threespine sticklebacks have a simple chromosomal mechanism for sex determination based on a nascent Y chromosome that is less than 10 million years old. Further analysis of the stickleback system will provide an exciting window into the evolution of sex-determination pathways and sex chromosomes in vertebrates.
View details for Web of Science ID 000223586900019
View details for PubMedID 15324658
The genetic architecture of parallel armor plate reduction in threespine sticklebacks.
2004; 2 (5): E109-?
How many genetic changes control the evolution of new traits in natural populations? Are the same genetic changes seen in cases of parallel evolution? Despite long-standing interest in these questions, they have been difficult to address, particularly in vertebrates. We have analyzed the genetic basis of natural variation in three different aspects of the skeletal armor of threespine sticklebacks (Gasterosteus aculeatus): the pattern, number, and size of the bony lateral plates. A few chromosomal regions can account for variation in all three aspects of the lateral plates, with one major locus contributing to most of the variation in lateral plate pattern and number. Genetic mapping and allelic complementation experiments show that the same major locus is responsible for the parallel evolution of armor plate reduction in two widely separated populations. These results suggest that a small number of genetic changes can produce major skeletal alterations in natural populations and that the same major locus is used repeatedly when similar traits evolve in different locations.
View details for PubMedID 15069472
Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks
2004; 428 (6984): 717-723
Hindlimb loss has evolved repeatedly in many different animals by means of molecular mechanisms that are still unknown. To determine the number and type of genetic changes underlying pelvic reduction in natural populations, we carried out genetic crosses between threespine stickleback fish with complete or missing pelvic structures. Genome-wide linkage mapping shows that pelvic reduction is controlled by one major and four minor chromosome regions. Pitx1 maps to the major chromosome region controlling most of the variation in pelvic size. Pelvic-reduced fish show the same left-right asymmetry seen in Pitx1 knockout mice, but do not show changes in Pitx1 protein sequence. Instead, pelvic-reduced sticklebacks show site-specific regulatory changes in Pitx1 expression, with reduced or absent expression in pelvic and caudal fin precursors. Regulatory mutations in major developmental control genes may provide a mechanism for generating rapid skeletal changes in natural populations, while preserving the essential roles of these genes in other processes.
View details for DOI 10.1038/nature02415
View details for Web of Science ID 000220823800030
View details for PubMedID 15085123
A general approach for identifying distant regulatory elements applied to the Gdf6 gene
2003; 13 (9): 2069-2081
Regulatory sequences in higher genomes can map large distances from gene coding regions, and cannot yet be identified by simple inspection of primary DNA sequence information. Here we describe an efficient method of surveying large genomic regions for gene regulatory information, and subdividing complex sets of distant regulatory elements into smaller intervals for detailed study. The mouse Gdf6 gene is expressed in a number of distinct embryonic locations that are involved in the patterning of skeletal and soft tissues. To identify sequences responsible for Gdf6 regulation, we first isolated a series of overlapping bacterial artificial chromosomes (BACs) that extend varying distances upstream and downstream of the gene. A LacZ reporter cassette was integrated into the Gdf6 transcription unit of each BAC using homologous recombination in bacteria. Each modified BAC was injected into fertilized mouse eggs, and founder transgenic embryos were analyzed for LacZ expression mid-gestation. The overlapping segments defined by the BAC clones revealed five separate regulatory regions that drive LacZ expression in 11 distinct anatomical locations. To further localize sequences that control expression in developing skeletal joints, we created a series of BAC constructs with precise deletions across a putative joint-control region. This approach further narrowed the critical control region to an area containing several stretches of sequence that are highly conserved between mice and humans. A distant 2.9-kilobase fragment containing the highly conserved regions is able to direct very specific expression of a minimal promoter/LacZ reporter in proximal limb joints. These results demonstrate that even distant, complex regulatory sequences can be identified using a combination of BAC scanning, BAC deletion, and comparative sequencing approaches.
View details for DOI 10.1101/gr.1306003
View details for Web of Science ID 000185085300010
View details for PubMedID 12915490
Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes
2003; 254 (1): 116-130
Growth/differentiation factors 5, 6, and 7 (GDF5/6/7) represent a distinct subgroup within the bone morphogenetic protein (BMP) family of secreted signaling molecules. Previous studies have shown that the Gdf5 gene is expressed in transverse stripes across developing skeletal elements and is one of the earliest known markers of joint formation during embryonic development. Although null mutations in this gene disrupt formation of some bones and joints in the skeleton, many sites are unaffected. Here, we show that the closely related family members Gdf6 and Gdf7 are expressed in different subsets of developing joints. Inactivation of the Gdf6 gene causes defects in joint, ligament, and cartilage formation at sites distinct from those seen in Gdf5 mutants, including the wrist and ankle, the middle ear, and the coronal suture between bones in the skull. Mice lacking both Gdf5 and Gdf6 show additional defects, including severe reduction or loss of some skeletal elements in the limb, additional fusions between skeletal structures, scoliosis, and altered cartilage in the intervertebral joints of the spinal column. These results show that members of the GDF5/6/7 subgroup are required for normal formation of bones and joints in the limbs, skull, and axial skeleton. The diverse effects on joint development and the different types of joints affected in the mutants suggest that members of the GDF family play a key role in establishing boundaries between many different skeletal elements during normal development. Some of the skeletal defects seen in single or double mutant mice resemble defects seen in human skeletal diseases, which suggests that these genes may be candidates that underlie some forms of carpal/tarsal coalition, conductive deafness, scoliosis, and craniosynostosis.
View details for Web of Science ID 000180731500009
View details for PubMedID 12606286
The genetic architecture of divergence between threespine stickleback species
2001; 414 (6866): 901-905
The genetic and molecular basis of morphological evolution is poorly understood, particularly in vertebrates. Genetic studies of the differences between naturally occurring vertebrate species have been limited by the expense and difficulty of raising large numbers of animals and the absence of molecular linkage maps for all but a handful of laboratory and domesticated animals. We have developed a genome-wide linkage map for the three-spined stickleback (Gasterosteus aculeatus), an extensively studied teleost fish that has undergone rapid divergence and speciation since the melting of glaciers 15,000 years ago. Here we use this map to analyse the genetic basis of recently evolved changes in skeletal armour and feeding morphologies seen in the benthic and limnetic stickleback species from Priest Lake, British Columbia. Substantial alterations in spine length, armour plate number, and gill raker number are controlled by genetic factors that map to independent chromosome regions. Further study of these regions will help to define the number and type of genetic changes that underlie morphological diversification during vertebrate evolution.
View details for Web of Science ID 000172813300044
View details for PubMedID 11780061
Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1
2001; 159 (2): 715-726
The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb.
View details for Web of Science ID 000171744900024
View details for PubMedID 11606546
The BMP family member Gdf7 is required for seminal vesicle growth, branching morphogenesis, and cytodifferentiation
2001; 234 (1): 138-150
Epithelial-mesenchymal interactions play an important role in the development of many different organs and tissues. The secretory glands of the male reproductive system, including the prostate and seminal vesicles, are derived from epithelial precursors. Signals from the underlying mesenchyme are required for normal growth, branching, and differentiation of the seminal vesicle epithelium. Here, we show that a member of the BMP family, Gdf7, is required for normal seminal vesicle development. Expression and tissue recombination experiments suggest that Gdf7 is a mesenchymal signal that acts in a paracrine fashion to control the differentiation of the seminal vesicle epithelium.
View details for DOI 10.1006/dbio.2001.0244
View details for Web of Science ID 000169059300011
View details for PubMedID 11356025
A large-scale in situ screen provides molecular evidence for the induction of eye anterior segment structures by the developing lens
2001; 231 (1): 63-76
The anterior segment of the vertebrate eye includes the cornea, iris, ciliary body, trabecular meshwork, and lens. Although malformations of these structures have been implicated in many human eye diseases, little is known about the molecular mechanisms that control their development. To identify genes involved in anterior segment formation, we developed a large-scale in situ hybridization screen and examined the spatial and temporal expression of over 1000 genes during eye development. This screen identified 62 genes with distinct expression patterns in specific eye structures, including several expressed in novel patterns in the anterior segment. Using these genes as developmental markers, we tested for the presence of inductive signals that control the differentiation of anterior segment tissues. Organ culture recombination experiments showed that a chick lens is capable of inducing the expression of markers of the presumptive iris and ciliary body in the developing mouse neural retina. The inducing activity from the lens acts only over short ranges and is present at multiple stages of eye development. These studies provide molecular evidence that an evolutionarily conserved signal from the lens controls tissue specification in the developing optic cup.
View details for Web of Science ID 000167271000005
View details for PubMedID 11180952
Genetic control of bone and joint formation.
Novartis Foundation symposium
2001; 232: 213-222
The form and pattern of the vertebrate skeleton is thought to be strongly influenced by several fundamental morphogenetic behaviours of mesenchymal cells during embryonic development. Recent genetic and developmental studies have identified some of the genes that play an important role in controlling both the aggregation of mesenchymal cells into rough outlines of future skeletal elements (condensations), and in controlling where skeletal precursors cleave or segment to produce separate skeletal elements connected by joints. Members of the bone morphogenetic protein (BMP) family appear to play an important role in both processes. Mouse and human mutations in these genes lead to defects in formation of specific bones and joints, with striking specificity for particular anatomical locations. Results from a range of experiments suggest that these molecules may have multiple functions during normal skeletal development and patterning. A major challenge for the future is to identify genes and pathways that can maintain, repair, or stimulate the regeneration of bone and joint structures at later developmental stages.
View details for PubMedID 11277082
A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of Hemimelic extra-toes mutant mice
2000; 67 (1): 19-27
Polydactyly is a common malformation of vertebrate limbs. In humans a major locus for nonsyndromic pre-axial polydactyly (PPD) has been mapped previously to 7q36. The mouse Hemimelic extra-toes (Hx) mutation maps to a homologous chromosome segment and has been proposed to affect a homologous gene. To understand the molecular changes underlying PPD, we used a positional cloning approach to identify the gene or genes disrupted by the Hx mutation and a closely linked limb mutation, Hammertoe (Hm). High resolution genetic mapping identified a small candidate interval for the mouse mutations located 1.2 cM distal to the Shh locus. The nonrecombinant interval was completely cloned in bacterial artificial chromosomes and searched for genes using a combination of exon trapping, sample sequencing, and mapping of known genes. Two novel genes, Lmbr1 and Lmbr2, are entirely within the candidate interval we defined genetically. The open reading frame of both genes is intact in mutant mice, but the expression of the Lmbr1 gene is dramatically altered in developing limbs of Hx mutant mice. The correspondence between the spatial and temporal changes in Lmbr1 expression and the embryonic onset of the Hx mutant phenotype suggests that the mouse Hx mutation may be a regulatory allele of Lmbr1. The human ortholog of Lmbr1 maps within the recently described interval for human PPD, strengthening the possibility that both mouse and human limb abnormalities are due to defects in the same highly conserved gene.
View details for Web of Science ID 000088195500003
View details for PubMedID 10945466
Efficient studies of long-distance Bmp5 gene regulation using bacterial artificial chromosomes
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2000; 97 (4): 1612-1617
The regulatory regions surrounding many genes may be large and difficult to study using standard transgenic approaches. Here we describe the use of bacterial artificial chromosome clones to rapidly survey hundreds of kilobases of DNA for potential regulatory sequences surrounding the mouse bone morphogenetic protein-5 (Bmp5) gene. Simple coinjection of large insert clones with lacZ reporter constructs recapitulates all of the sites of expression observed previously with numerous small constructs covering a large, complex regulatory region. The coinjection approach has made it possible to rapidly survey other regions of the Bmp5 gene for potential control elements, to confirm the location of several elements predicted from previous expression studies using regulatory mutations at the Bmp5 locus, to test whether Bmp5 control regions act similarly on endogenous and foreign promoters, and to show that Bmp5 control elements are capable of rescuing phenotypic effects of a Bmp5 deficiency. This rapid approach has identified new Bmp5 control regions responsible for controlling the development of specific anatomical structures in the vertebrate skeleton. A similar approach may be useful for studying complex control regions surrounding many other genes important in embryonic development and human disease.
View details for Web of Science ID 000085409600060
View details for PubMedID 10677507
GDF5 coordinates bone and joint formation during digit development
1999; 209 (1): 11-27
A functional skeletal system requires the coordinated development of many different tissue types, including cartilage, bones, joints, and tendons. Members of the Bone morphogenetic protein (BMP) family of secreted signaling molecules have been implicated as endogenous regulators of skeletal development. This is based on their expression during bone and joint formation, their ability to induce ectopic bone and cartilage, and the skeletal abnormalities present in animals with mutations in BMP family members. One member of this family, Growth/differentiation factor 5 (GDF5), is encoded by the mouse brachypodism locus. Mice with mutations in this gene show reductions in the length of bones in the limbs, altered formation of bones and joints in the sternum, and a reduction in the number of bones in the digits. The expression pattern of Gdf5 during normal development and the phenotypes seen in mice with single or double mutations in Gdf5 and Bmp5 suggested that Gdf5 has multiple functions in skeletogenesis, including roles in joint and cartilage development. To further understand the function of GDF5 in skeletal development, we assayed the response of developing chick and mouse limbs to recombinant GDF5 protein. The results from these assays, coupled with an analysis of the development of brachypodism digits, indicate that GDF5 is necessary and sufficient for both cartilage development and the restriction of joint formation to the appropriate location. Thus, GDF5 function in the digits demonstrates a link between cartilage development and joint development and is an important determinant of the pattern of bones and articulations in the digits.
View details for Web of Science ID 000079924400002
View details for PubMedID 10208739
An extensive 3 ' regulatory region controls expression of Bmp5 in specific anatomical structures of the mouse embryo
1998; 148 (1): 401-408
Bone morphogenetic proteins (BMPs) are secreted signaling molecules that control important developmental events in many different organisms. Previous studies have shown that BMPs are expressed at the earliest stages of skeletal development, and are required for formation of specific skeletal features, strongly suggesting that they are endogenous signals used to control formation of skeletal tissue. Despite the importance of BMP signaling in normal development, very little is known about the mechanisms that control the synthesis and distribution of BMP signals in vertebrates. Here, we identify a large array of cis-acting control sequences that lay out expression of the mouse Bmp5 gene in specific skeletal structures and soft tissues. Some of these elements show striking specificity for particular anatomical features within the skeleton, rather than for cartilage and bone in general. These data suggest that the vertebrate skeleton is built from the sum of many independent domains of BMP expression, each of which may be controlled by separate regulatory elements driving expression at specific anatomical locations. Surprisingly, some of the regulatory sequences in the Bmp5 gene map over 270 kb from the Bmp5 promoter, making them among the most distant elements yet identified in studies of eukaryotic gene expression.
View details for Web of Science ID 000071494000037
View details for PubMedID 9475750
- The Bmp8 gene is expressed in developing skeletal tissue and maps near the Achondroplasia locus on mouse chromosome 4 GENOMICS 1997; 40 (1): 196-198
Spectrum of Bmp5 mutations from germline mutagenesis experiments in mice
1997; 145 (2): 435-443
Over 40 years of mutagenesis experiments using the mouse specific-locus test have produced a large number of induced germline mutations at seven loci, among them the short ear locus. We have previously shown that the short ear locus encodes bone morphogenetic protein 5 (BMP5), a member of a large family of secreted signaling molecules that play key roles in axis formation, tissue differentiation, mesenchymalepithelial interactions, and skeletal development. Here we examine 24 chemical- and radiation-induced mutations at the short ear locus. Sequence changes in the Bmp5 open reading frame confirm the importance of cysteine residues in the function of TGF beta superfamily members. The spectrum of N-ethyl-N-nitrosourea-induced mutations also provides new information about the basepair, sequence context, and strand specificity of germline mutations in mammals.
View details for Web of Science ID A1997WM59900019
View details for PubMedID 9071596
Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family
1996; 122 (12): 3969-3979
The mouse brachypodism locus encodes a bone morphogenetic protein (BMP)-like molecule called growth/differentiation factor 5 (GDF5). Here we show that Gdf5 transcripts are expressed in a striking pattern of transverse stripes within many skeletal precursors in the developing limb. The number, location and time of appearance of these stripes corresponds to the sites where joints will later form between skeletal elements. Null mutations in Gdf5 disrupt the formation of more than 30% of the synovial joints in the limb, leading to complete or partial fusions between particular skeletal elements, and changes in the patterns of repeating structures in the digits, wrists and ankles. Mice carrying null mutations in both Gdf5 and another BMP family member, Bmp5, show additional abnormalities not observed in either of the single mutants. These defects include disruption of the sternebrae within the sternum and abnormal formation of the fibrocartilaginous joints between the sternebrae and ribs. Previous studies have shown that members of the BMP family are required for normal development of cartilage and bone. The current studies suggest that particular BMP family members may also play an essential role in the segmentation process that cleaves skeletal precursors into separate elements. This process helps determine the number of elements in repeating series in both limbs and sternum, and is required for normal generation of the functional articulations between many adjacent structures in the vertebrate skeleton.
View details for Web of Science ID A1996WC55400028
View details for PubMedID 9012517
- The role of BMPs and GDFs in development of region-specific skeletal structures NEW YORK ACAD SCIENCES. 1996: 70-79
CHROMOSOMAL LOCALIZATION, EMBRYONIC EXPRESSION, AND IMPRINTING TESTS FOR BMP7 ON DISTAL MOUSE CHROMOSOME-2
1995; 28 (3): 576-580
Murine Bmp7 has been assigned to distal Chromosome 2 by interspecific backcross mapping. The map location suggests close linkage to classical mouse mutations and places Bmp7 within a chromosome region thought to contain one or more unidentified imprinted genes. A direct test suggests that Bmp7 is not imprinted. An examination of embryonic RNA expression patterns shows that Bmp7 is expressed in a variety of skeletal and nonskeletal tissues. Both embryonic expression patterns and the human chromosomal sublocalization inferred from its mouse location make Bmp7 a candidate for the gene affected in some patients with Holt-Oram syndrome.
View details for Web of Science ID A1995RQ98900030
View details for PubMedID 7490098
BMP5 AND THE MOLECULAR, SKELETAL, AND SOFT-TISSUE ALTERATIONS IN SHORT EAR MICE
1994; 166 (1): 112-122
Mutations at the mouse short ear (se) locus alter the formation and repair of skeletal structures and the development of several soft tissues. Most of the developmental effects of the gene have been studied using a spontaneous mutation reported over 70 years ago. Here we show that this mutation consists of a nonsense mutation in a secreted signaling molecule called bone morphogenetic protein 5 (BMP5). This small sequence alteration, in combination with previously reported translocation and deletion mutations, provides strong genetic evidence that BMP5 is the normal product of the se locus. Transcripts from the Bmp5 gene are expressed at the earliest stages of normal skeletal development in patterns that closely resemble the shapes of forming skeletal elements. The gene is also expressed at several sites of soft tissue abnormalities previously reported in se animals, including lungs, liver, ureter, bladder, and intestines. The combined genetic, biochemical, and expression data suggest that BMP5 is a key signal used to initiate formation of particular skeletal elements and is required for normal development of several soft tissues as well.
View details for Web of Science ID A1994PT49200009
View details for PubMedID 7958439
LIMB ALTERATIONS IN BRACHYPODISM MICE DUE TO MUTATIONS IN A NEW MEMBER OF THE TGF-BETA-SUPERFAMILY
1994; 368 (6472): 639-643
The mutation brachypodism (bp) alters the length and number of bones in the limbs of mice but spares the axial skeleton. It illustrates the importance of specific genes in controlling the morphogenesis of individual skeletal elements in the tetrapod limb. We now report the isolation of three new members of the transforming growth factor-beta (TGF-beta) superfamily (growth/differentiation factors (GDF) 5,6 and 7) and show by mapping, expression patterns and sequencing that mutations in Gdf5 are responsible for skeletal alterations in bp mice. GDF5 and the closely related GDF6 and GDF7 define a new subgroup of factors related to known bone- and cartilage-inducing molecules, the bone morphogenetic proteins (BMPs). Studies of Bmp5 mutations in short ear mice have shown that at least one other BMP gene is also required for normal skeletal development. The highly specific skeletal alterations in bp and short ear mice suggest that different members of the BMP family control the formation of different morphological features in the mammalian skeleton.
View details for Web of Science ID A1994NF39200062
View details for PubMedID 8145850
- THE TGF-BETA SUPERFAMILY - NEW MEMBERS, NEW RECEPTORS, AND NEW GENETIC TESTS OF FUNCTION IN DIFFERENT ORGANISMS GENES & DEVELOPMENT 1994; 8 (2): 133-146
WHAT DO BMPS DO IN MAMMALS - CLUES FROM THE MOUSE SHORT-EAR MUTATION
TRENDS IN GENETICS
1994; 10 (1): 16-21
Bone morphogenetic proteins (BMPs) are a family of secreted signaling molecules that were originally isolated on the basis of their remarkable ability to induce the formation of ectopic bones when implanted into adult animals. The first mutations identified in a mammalian BMP gene suggest that members of this family induce the formation, patterning and repair of particular morphological features in higher animals.
View details for Web of Science ID A1994MR68900007
View details for PubMedID 8146910
Encyclopedia of the mouse genome III. October 1993. Mouse chromosome 9.
1993; 4: S136-53
View details for PubMedID 8268669
THE MOUSE SHORT-EAR SKELETAL MORPHOGENESIS LOCUS IS ASSOCIATED WITH DEFECTS IN A BONE MORPHOGENETIC MEMBER OF THE TGF-BETA SUPERFAMILY
1992; 71 (3): 399-410
The mouse short ear gene is required for normal growth and patterning of skeletal structures, and for repair of bone fractures in adults. We have carried out an extensive chromosome walk in the chromosome region that surrounds this locus. Here we show that the short ear region contains the gene for a TGF beta-related protein called bone morphogenetic protein 5 (Bmp-5). This gene is deleted or rearranged in several independent mutations at the short ear locus. Mice homozygous for large deletions of the Bmp-5 coding region are viable and fertile. Mutations at the short ear locus provide an important new tool for defining the normal functions of BMPs in mammals. The specific skeletal defects seen in short-eared animals, which occur against a background of otherwise normal skeletal structures, suggest that particular aspects of skeletal morphology may be determined by individual members of a family of signaling factors that can induce the formation of cartilage and bone in vivo.
View details for Web of Science ID A1992JW43500007
View details for PubMedID 1339316
- MOUSE CHROMOSOME-9 SPRINGER VERLAG. 1992: S136-S152
Mouse chromosome 9.
1991; 1: S127-45
View details for PubMedID 1799796