Yanmin Yang

All Publications

• Giant axonal neuropathy CELLULAR AND MOLECULAR LIFE SCIENCES Yang, Y., Allen, E., Ding, J., Wang, W. 2007; 64 (5): 601-609

  Abstract

  Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder affecting both the central and peripheral nervous systems. Cytopathologically, the disorder is characterized by giant axons with derangements of cytoskeletal components. Geneticists refined the chromosomal interval containing the locus, culminating in the cloning of the defective gene, GAN. To date, many distinct mutations scattered throughout the coding region of the locus have been reported by researchers from different groups around the world. GAN encodes the protein, gigaxonin. Recently, a genetic mouse model of the disease was generated by targeted disruption of the locus. Over the years, the molecular mechanisms underlying GAN have attracted much interest. Studies have revealed that gigaxonin appears to play an important role in cytoskeletal functions and dynamics by directing ubiquitin-mediated degradations of cytoskeletal proteins. Aberrant accumulations of cytoskeletal-associated proteins caused by a defect in the ubiquitin-proteasome system (UPS) have been shown to be responsible for neurodegeneration occurring in GAN-null neurons, providing strong support for the notion that UPS plays crucial roles in cytoskeletal functions and dynamics. However, many key questions about the disease remain unanswered.

  View details for DOI 10.1007/s00018-007-6396-4

  View details for Web of Science ID 000244713900009

  View details for PubMedID 17256086

• Retrolinkin, a membrane protein, plays an important role in retrograde axonal transport PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liu, J., Ding, J., Wu, C., Bhagavatula, P., Cui, B., Chu, S., Mobley, W. C., Yang, Y. 2007; 104 (7): 2223-2228

  Abstract

  Retrograde axonal transport plays an important role in the maintenance of neuronal functions, but the mechanism is poorly defined partly because the constituents of the retrograde transport system and their interactions have yet to be elucidated. Of special interest is how dynein/dynactin motor proteins interact with membrane cargoes. Here, we report that an endosomal vesicle protein, termed retrolinkin, functions as a receptor tethering vesicles to dynein/dynactin through BPAG1n4. Retrolinkin, a membrane protein highly enriched in neuronal endosomes, binds directly to BPAG1n4. Deletion of retrolinkin membrane-association domains disrupts retrograde vesicular transport, recapitulating the BPAG1 null phenotype. We propose that retrolinkin acts with BPAG1n4 to specifically regulate retrograde axonal transport. Our work lays the foundation for understanding fundamental issues of axonal transport and provides insights into the molecular mechanisms underlying human neurodegenerative disorders.

  View details for DOI 10.1073/pnas.0602222104

  View details for Web of Science ID 000244438500035

  View details for PubMedID 17287360

  View details for PubMedCentralID PMC1892971

• Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport HUMAN MOLECULAR GENETICS Ding, J. Q., Allen, E., Wang, W., Valle, A., Wu, C. B., Nardine, T., Cui, B. X., Yi, J., Taylor, A., Jeon, N. L., Chu, S., So, Y., Vogel, H., Tolwani, R., Mobley, W., Yang, Y. M. 2006; 15 (9): 1451-1463

  Abstract

  Mutations in gigaxonin were identified in giant axonal neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.

  View details for DOI 10.1093/hmg/ddl069

  View details for PubMedID 16565160

• Microtubule-associated protein 8 contains two microtubule binding sites BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Ding, J. Q., Valle, A., Allen, E., Wang, W., Nardine, T., Zhang, Y. J., Peng, L. L., Yang, Y. M. 2006; 339 (1): 172-179

  Abstract

  Microtubule-associated proteins (MAPs) are critical regulators of microtubule dynamics and functions, and have long been proposed to be essential for many cellular events including neuronal morphogenesis and functional maintenance. In this study, we report the characterization of a new microtubule-associated protein, we named MAP8. The protein of MAP8 is mainly restricted to the nervous system postnatally in mouse. Its expression could first be detected as early as at embryonic day 10, levels plateau during late embryonic and neonatal periods, and subsequently decrease moderately to remain constant into adulthood. In addition to its carboxyl terminal binding site, the MAP8 polyprotein also contains a functional microtubule-binding domain at its N-terminal segment. The association of the carboxyl terminal of the light chain with actin microfilaments could also be detected. Our findings define MAP8 as a novel microtubule associated protein containing two microtubule binding domains.

  View details for DOI 10.1016/j.bbrc.2005.10.199

  View details for PubMedID 16297881

• Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway CURRENT BIOLOGY Wang, W., Ding, J. Q., Allen, E., Zhu, P., Zhang, L., Vogel, H., Yang, Y. M. 2005; 15 (22): 2050-2055

  Abstract

  Gigaxonin is mutated in human giant axonal neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.

  View details for DOI 10.1016/j.cub.2005.10.052

  View details for PubMedID 16303566

• Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival NATURE Allen, E., Ding, J. Q., Wang, W., Pramanik, S., Chou, J., Yau, V., Yang, Y. M. 2005; 438 (7065): 224-228

  Abstract

  Giant axonal neuropathy (GAN) is a devastating sensory and motor neuropathy caused by mutations in the GAN gene, which encodes the ubiquitously expressed protein gigaxonin. Cytopathological features of GAN include axonal degeneration, with accumulation and aggregation of cytoskeletal components. Little is currently known about the molecular mechanisms underlying this recessive disorder. Here we show that gigaxonin controls protein degradation, and is essential for neuronal function and survival. We present evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein 1B (MAP1B). Overexpression of gigaxonin leads to enhanced degradation of MAP1B-LC, which can be antagonized by proteasome inhibitors. Ablation of gigaxonin causes a substantial accumulation of MAP1B-LC in GAN-null neurons. Moreover, we show that overexpression of MAP1B in wild-type cortical neurons leads to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improves the survival rate of null neurons. Our results identify gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-LC degradation, and provide insight into the molecular mechanisms underlying human neurodegenerative disorders.

  View details for DOI 10.1038/nature04256

  View details for Web of Science ID 000233133500049

  View details for PubMedID 16227972

• BPAG1 n4 is essential for retrograde axonal transport in sensory neurons JOURNAL OF CELL BIOLOGY Liu, J. J., Ding, J. Q., Kowal, A. S., Nardine, T., Allen, E., Delcroix, J. D., Wu, C. B., Mobley, W., Fuchs, E., Yang, Y. M. 2003; 163 (2): 223-229

  Abstract

  Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.

  View details for DOI 10.1083/jcb.200306075

  View details for Web of Science ID 000186331100004

  View details for PubMedID 14581450

  View details for PubMedCentralID PMC2173519

• Microtubule-associated protein 1B: a neuronal binding partner for gigaxonin JOURNAL OF CELL BIOLOGY Ding, J. Q., Liu, J. J., Kowal, A. S., Nardine, T., Bhattacharya, P., Lee, A., Yang, Y. M. 2002; 158 (3): 427-433

  Abstract

  Giant axonal neuropathy (GAN), an autosomal recessive disorder caused by mutations in GAN, is characterized cytopathologically by cytoskeletal abnormality. Based on its sequence, gigaxonin contains an NH2-terminal BTB domain followed by six kelch repeats, which are believed to be important for protein-protein interactions (Adams, J., R. Kelso, and L. Cooley. 2000. Trends Cell Biol. 10:17-24.). Here, we report the identification of a neuronal binding partner of gigaxonin. Results obtained from yeast two-hybrid screening, cotransfections, and coimmunoprecipitations demonstrate that gigaxonin binds directly to microtubule-associated protein (MAP)1B light chain (LC; MAP1B-LC), a protein involved in maintaining the integrity of cytoskeletal structures and promoting neuronal stability. Studies using double immunofluorescent microscopy and ultrastructural analysis revealed physiological colocalization of gigaxonin with MAP1B in neurons. Furthermore, in transfected cells the specific interaction of gigaxonin with MAP1B is shown to enhance the microtubule stability required for axonal transport over long distance. At least two different mutations identified in GAN patients (Bomont, P., L. Cavalier, F. Blondeau, C. Ben Hamida, S. Belal, M. Tazir, E. Demir, H. Topaloglu, R. Korinthenberg, B. Tuysuz, et al. 2000. Nat. Genet. 26:370-374.) lead to loss of gigaxonin-MAP1B-LC interaction. The devastating axonal degeneration and neuronal death found in GAN patients point to the importance of gigaxonin for neuronal survival. Our findings may provide important insights into the pathogenesis of neurodegenerative disorders related to cytoskeletal abnormalities.

  View details for DOI 10.1083/jcb.200202055

  View details for Web of Science ID 000177329900008

  View details for PubMedID 12147674

  View details for PubMedCentralID PMC2173828

• An epidermal plakin that integrates actin and microtubule networks at cellular junctions JOURNAL OF CELL BIOLOGY Karakesisoglou, I., Yang, Y. M., Fuchs, E. 2000; 149 (1): 195-208

  Abstract

  Plakins are cytoskeletal linker proteins initially thought to interact exclusively with intermediate filaments (IFs), but recently were found to associate additionally with actin and microtubule networks. Here, we report on ACF7, a mammalian orthologue of the Drosophila kakapo plakin genetically involved in epidermal-muscle adhesion and neuromuscular junctions. While ACF7/kakapo is divergent from other plakins in its IF-binding domain, it has at least one actin (K(d) = 0.35 microM) and one microtubule (K(d) approximately 6 microM) binding domain. Similar to its fly counterpart, ACF7 is expressed in the epidermis. In well spread epidermal keratinocytes, ACF7 discontinuously decorates the cytoskeleton at the cell periphery, including microtubules (MTs) and actin filaments (AFs) that are aligned in parallel converging at focal contacts. Upon calcium induction of intercellular adhesion, ACF7 and the cytoskeleton reorganize at cell-cell borders but with different kinetics from adherens junctions and desmosomes. Treatments with cytoskeletal depolymerizing drugs reveal that ACF7's cytoskeletal association is dependent upon the microtubule network, but ACF7 also appears to stabilize actin at sites where microtubules and microfilaments meet. We posit that ACF7 may function in microtubule dynamics to facilitate actin-microtubule interactions at the cell periphery and to couple the microtubule network to cellular junctions. These attributes provide a clear explanation for the kakapo mutant phenotype in flies.

  View details for Web of Science ID 000086303800019

  View details for PubMedID 10747097

• Crossroads can cytoskeletal highways CELL Fuchs, E., Yang, Y. M. 1999; 98 (5): 547-550

  View details for Web of Science ID 000082433500001

  View details for PubMedID 10490093

• Integrators of the cytoskeleton that stabilize microtubules CELL Yang, Y. M., Bauer, C., Strasser, G., Wollman, R., Julien, J. P., Fuchs, E. 1999; 98 (2): 229-238

  Abstract

  Sensory neurodegeneration occurs in mice defective in BPAG1, a gene encoding cytoskeletal linker proteins capable of anchoring neuronal intermediate filaments to actin cytoskeleton. While BPAG1 null mice fail to anchor neurofilaments (NFs), BPAG1/NF null mice still degenerate in the absence of NFs. We report a novel neural splice form that lacks the actin-binding domain and instead binds and stabilizes microtubules. This interaction is functionally important; in mice and in vitro, neurons lacking BPAG1 display short, disorganized, and unstable microtubules defective in axonal transport. Ironically, BPAG1 neural isoforms represent microtubule-associated proteins that when absent lead to devastating consequences. Moreover, BPAG1 can functionally account for the extraordinary stability of axonal microtubules necessary for transport over long distances. Its isoforms interconnect all three cytoskeletal networks, a feature apparently central to neuronal survival.

  View details for Web of Science ID 000081632300012

  View details for PubMedID 10428034

• A dysfunctional desmin mutation in a patient with severe generalized myopathy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Munoz-Marmol, A. M., Strasser, G., Isamat, M., Coulombe, P. A., Yang, Y. M., Roca, X., Vela, E., Mate, J. L., Coll, J., Fernandez-Figueras, M. T., Navas-Palacios, J. J., Ariza, A., Fuchs, E. 1998; 95 (19): 11312-11317

  Abstract

  Mice lacking desmin produce muscle fibers with Z disks and normal sarcomeric organization. However, the muscles are mechanically fragile and degenerate upon repeated contractions. We report here a human patient with severe generalized myopathy and aberrant intrasarcoplasmic accumulation of desmin intermediate filaments. Muscle tissue from this patient lacks the wild-type desmin allele and has a desmin gene mutation encoding a 7-aa deletion within the coiled-coil segment of the protein. We show that recombinant desmin harboring this deletion cannot form proper desmin intermediate filament networks in cultured cells, nor is it able to assemble into 10-nm filaments in vitro. These findings provide direct evidence that a mutation in desmin can cause human myopathies.

  View details for Web of Science ID 000075957100056

  View details for PubMedID 9736733

• Developmental expression of BPAG1-n: Insights into the spastic ataxia and gross neurologic degeneration in dystonia musculorum mice DEVELOPMENTAL BIOLOGY Dowling, J., Yang, Y. M., Wollmann, R., Reichardt, L. F., Fuchs, E. 1997; 187 (2): 131-142

  Abstract

  Ablation of the BPAG1 gene results in the dystonia musculorum mouse, exhibiting rapid spinal nerve degeneration, dystonic movements, and severe ataxia. By defining the developmental and tissue-specific expression of the neuronal form of BPAG1 (BPAG1-n) and by comparing the corresponding pathology in BPAG1 null mice, we seek here to understand how absence of BPAG1 results in this devastating phenotype in mice and in potentially related human neurological disorders. Throughout normal development, BPAG1-n was expressed in a variety of sensory and autonomic neuronal structures, but was absent or reduced in areas such as basal ganglia that are often affected in dystonias and ataxias. Interestingly, BPAG1-n was also expressed broadly in embryonic motor neurons, but expression declined dramatically after birth. Despite these complex developmental patterns, BPAG1-/- pathology was restricted largely to postnatal development. Moreover, gross neuronal degeneration was restricted to only a few regions where BPAG1-n was found, including dorsal root ganglion neurons and a small subset of motor neurons. Most notably, while skeletal muscle was normal, appearance of severe dystonic ataxia correlated with postnatal degeneration of muscle spindles. Collectively, our findings suggest a mechanism for the BPAG1 null phenotype and indicate that different neurons respond differently to the absence of BPAG1-n, a cytoskeletal linker protein.

  View details for Web of Science ID A1997XM60100001

  View details for PubMedID 9242412

• Intermediate filament linker proteins 50th Annual Symposium of the Society-of-General-Physiologists - Cytoskeletal Regulation of Membrane Function Fuchs, E., Yang, Y. M., Dowling, J., Kouklis, P., Smith, E., Guo, L. F., Yu, Q. C. ROCKEFELLER UNIV PRESS. 1997: 141–148

  View details for Web of Science ID A1997BJ08L00011

  View details for PubMedID 9210226

• An essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments CELL Yang, Y. M., Dowling, J., Yu, Q. C., Kouklis, P., Cleveland, D. W., Fuchs, E. 1996; 86 (4): 655-665

  Abstract

  Typified by rapid degeneration of sensory neurons, dystonia musculorum mice have a defective BPAG1 gene, known to be expressed in epidermis. We report a neuronal splice form, BPAG1n, which localizes to sensory axons. Both isoforms have a coiled-coil rod, followed by a carboxy domain that associates with intermediate filaments. However, the amino terminus of BPAG1n differs from BPAG1e in that it contains a functional actin-binding domain. In transfected cells, BPAG1n coaligns neurofilaments and microfilaments, establishing this as a cytoskeletal protein interconnecting actin and intermediate filament cytoskeletons. In BPAG1 null mice, axonal architecture is markedly perturbed, consistent with a failure to tether neurofilaments to the actin cytoskeleton and underscoring the physiological relevance of this protein.

  View details for Web of Science ID A1996VE23500015

  View details for PubMedID 8752219

• SEQUENTIAL REQUIREMENT OF HEPATOCYTE GROWTH-FACTOR AND NEUREGULIN IN THE MORPHOGENESIS AND DIFFERENTIATION OF THE MAMMARY-GLAND JOURNAL OF CELL BIOLOGY Yang, Y. M., Spitzer, E., Meyer, D., Sachs, M., Niemann, C., Hartmann, G., Weidner, K. M., Birchmeier, C., BIRCHMEIER, W. 1995; 131 (1): 215-226

  Abstract

  We have examined the role of two mesenchymal ligands of epithelial tyrosine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promoted branching of the ductal trees but inhibited the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland could be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recombinant HGF and NRG. We thus show that two major postnatal morphogenic periods of mammary gland development are dependent on sequential mesenchymal-epithelial interactions mediated by HGF and NRG.

  View details for Web of Science ID A1995RX83700018

  View details for PubMedID 7559778

• MEMBERS OF THE FATTY-ACID-BINDING PROTEIN FAMILY ARE DIFFERENTIATION FACTORS FOR THE MAMMARY-GLAND JOURNAL OF CELL BIOLOGY Yang, Y. M., Spitzer, E., Kenney, N., Zschiesche, W., Li, M. L., Kromminga, A., Muller, T., Spener, F., LEZIUS, A., Veerkamp, J. H., Smith, G. H., SALOMON, D. S., Grosse, R. 1994; 127 (4): 1097-1109

  Abstract

  Mammary gland development is controlled by systemic hormones and by growth factors that might complement or mediate hormonal action. Peptides that locally signal growth cessation and stimulate differentiation of the developing epithelium have not been described. Here, we report that recombinant and wild-type forms of mammary-derived growth inhibitor (MDGI) and heart-fatty acid binding protein (FABP), which belong to the FABP family, specifically inhibit growth of normal mouse mammary epithelial cells (MEC), while growth of stromal cells is not suppressed. In mammary gland organ culture, inhibition of ductal growth is associated with the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures. In parallel, MDGI stimulates its own expression and promotes milk protein synthesis. Selective inhibition of endogenous MDGI expression in MEC by antisense phosphorothioate oligonucleotides suppresses appearance of alveolar end buds and lowers the beta-casein level in organ cultures. Furthermore, MDGI suppresses the mitogenic effects of epidermal growth factor, and epidermal growth factor antagonizes the activities of MDGI. Finally, the regulatory properties of MDGI can be fully mimicked by an 11-amino acid sequence, represented in the COOH terminus of MDGI and a subfamily of structurally related FABPs. This peptide does not bind fatty acids. To our knowledge, this is the first report about a growth inhibitor promoting mammary gland differentiation.

  View details for Web of Science ID A1994PT48300017

  View details for PubMedID 7962070