Bio


Dr Liakath-Ali holds a PhD degree in molecular genetics from the University of Cambridge, UK. He carried out his doctoral and a brief post-doctoral research under the supervision of Professor Fiona Watt at Cambridge and King’s College London. While in Watt lab, he conducted a first, large-scale tissue-specific phenotype screen on hundreds of knockout mice and discovered many novel genes that are essential for mammalian skin function. He further elucidated the mechanistic roles of sphingolipid and a ribosome-rescue pathway in epidermal stem cell function. He has published many papers in the area of skin biology and won several awards, including, most recently a long-term fellowship from the European Molecular Biology Organization (EMBO).

Dr Liakath-Ali obtained his bachelor and master degree in Zoology from Jamal Mohamed College (Bharathidasan University), Trichy, India. He further specialized in human genetics and obtained an MPhil from the University of Madras, India. He went on to work at various capacities at Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India, Institute of Human Genetics, University of Göttingen, Germany and the Wellcome Sanger Institute, Cambridge, UK. Dr Liakath-Ali also holds a degree equivalent (Associateship of King’s College (AKC) in Philosophy, Ethics and Theology.

It is perhaps these combinations of diverse backgrounds and training that led Dr Liakath-Ali to develop an interest in fundamental questions in neuroscience. He is currently an EMBO Research Fellow, working under the supervision of Professor Thomas Südhof at Stanford on genetic mechanisms involved in synapse formation and function. He is also an avid communicator of science, STEM ambassador and open science advocate.

Honors & Awards


  • EMBO Long-Term Fellowship, European Molecular Biology Organisation (EMBO) (July 2018 - July 2020)
  • Blankenese Conference Stipend, Blankenese Conference, Hamburg, Germany (2018)
  • Zhongmei Chen Yong Travel Award for Scientific Excellence, International Society for Stem Cell Research (ISSCR) (2018)
  • eLIFE Early-Career Researcher Travel Grant, eLIFE (2018)
  • Honor Fell Travel awards, British Society for Cell Biology (2017, 2015, 2013)
  • Junior Scientist Travel Award, Genetics Society, UK (2017, 2015)
  • Scholarships, International Mammalian Genome Society (2017, 2015)
  • Best Poster Award at EMBO Conference, EMBO Conference on Protein Quality Control. Sant Feliu de Guixols, Spain (2017)
  • Canadian Stem Cell Network Travel Award, Canadian Stem Cell Network and Till & McCulloch stem cell meeting (2017)
  • Image of Distinction, Nikon Small World photomicrography awards (2017)
  • Best Talk Award, Lipidomics Forum, Leibniz Institute for Analytical Research (ISAS), Dortmund, Germany (2016)
  • Eugene M. Farber Travel Award for Young Investigators, Society for Investigative Dermatology (2015)
  • Outstanding Presentation Award, International Mammalian Genome Conference, Yokohama, Japan (2015)
  • Presentation at the Houses of Parliament, UK, SET for Britain 2014 (Britain’s early-stage researchers competition) (2014)
  • Travel Award, Graduate School of Life Sciences, University of Cambridge (2014)
  • NIH-Mouse Genome Scholarship, International Mammalian Genome Society (2013)
  • Travel Grant, Royal Society of Biology (2013)
  • Santander Scholarship, Darwin College, University of Cambridge (2012-2015)
  • Travel and Participatory Award, OptiStem (Optimization of Stem cell Therapy for degenerative Epithelial and Muscle Diseases) (2012)
  • Research Internship, German Research Foundation (DFG), University of Göttingen (2007-2008)
  • Senior Research Fellowship, Lady Tata Memorial Trust, India (declined) (2007-2008)
  • Sambuvarayar Endowment Merit Scholarship, University of Madras, India (2003-2004)

Boards, Advisory Committees, Professional Organizations


  • Ambassador, eLIFE Early Career Researchers Community (2019 - Present)
  • Member, International Society for Stem Cell Research (ISSCR) (2018 - Present)
  • Member of Scientific Committee and Ambassador, The English Brain Bee – an organization to promote neuroscience education and research among school students. (2017 - Present)
  • STEM Ambassador, STEM Network, UK (2017 - Present)
  • eMentor, Social Mobility Foundation, UK (2017 - Present)
  • Resident Expert Biologist, Royal Society of Biology, UK (2016 - 2016)
  • Associate Member, EuroScience (European Association for the Advancement of Science and Technology) (2015 - Present)
  • Editor, Wattlab blog (2015 - 2018)
  • Member, Society for Developmental Biology (2014 - Present)
  • Honorary Member, Institute of Biomedical Sciences (UK) (2014 - 2015)
  • Full member, The Genetics Society, UK (2013 - Present)
  • Member, International Mammalian Genome Society (2013 - Present)
  • Member, American Society for Cell Biology (2013 - Present)
  • Faraday Student Member, The Royal Institution of Great Britain (2013 - 2017)
  • Member, Royal Society of Biology (2012 - Present)
  • Member, British Society for Cell Biology (2012 - Present)
  • Genome Campus Tour Leader, The Franklin Centre for Public Engagement, Wellcome Sanger Institute, Cambridge, UK (2009 - 2010)
  • Member, Indian Society of Human Genetics (2004 - 2005)
  • Student Secretary, The Zoology Association, Post Graduate & Research Department of Zoology, Jamal Mohamed College, Tiruchirappalli, India (2001 - 2003)

Professional Education


  • Doctor of Philosophy (PhD), University of Cambridge, UK, Molecular Genetics (Stem Cell Biology) (2015)
  • Associateship of King's College, King's College London, UK, Philosophy, Ethics & Theology (2015)
  • Master of Philosophy (MPhil), University of Madras, India, Genetics (2004)
  • Master of Science (MSc), Jamal Mohamed College, Bharathidasan University, Trichy, India, Zoology (2003)
  • Bachelor of Science (BSc), Jamal Mohamed College, Bharathidasan University, Trichy, India, Zoology (2001)

Lab Affiliations


All Publications


  • An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis NATURE Liakath-Ali, K., Mills, E. W., Sequeira, I., Lichtenberger, B. M., Pisco, A., Sipila, K. H., Mishra, A., Yoshikawa, H., Wu, C., Ly, T., Lamond, A. I., Adham, I. M., Green, R., Watt, F. M. 2018; 556 (7701): 376-+

    Abstract

    Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation1,2. Although these mechanisms have been extensively studied in yeast, little is known about their role in mammalian tissues, despite emerging evidence that stem cell fate is controlled by translational mechanisms3,4. One evolutionarily conserved component of the quality control machinery, Dom34 (in higher eukaryotes known as Pelota (Pelo)), rescues stalled ribosomes 5 . Here we show that Pelo is required for mammalian epidermal homeostasis. Conditional deletion of Pelo in mouse epidermal stem cells that express Lrig1 results in hyperproliferation and abnormal differentiation of these cells. By contrast, deletion of Pelo in Lgr5-expressing stem cells has no effect and deletion in Lgr6-expressing stem cells induces only a mild phenotype. Loss of Pelo results in accumulation of short ribosome footprints and global upregulation of translation, rather than affecting the expression of specific genes. Translational inhibition by rapamycin-mediated downregulation of mTOR (mechanistic target of rapamycin kinase) rescues the epidermal phenotype. Our study reveals that the ribosome-rescue machinery is important for mammalian tissue homeostasis and that it has specific effects on different stem cell populations.

    View details for PubMedID 29643507

  • Myosin 10 is involved in murine pigmentation. Experimental dermatology Liakath-Ali, K., Vancollie, V. E., Sequeira, I., Lelliott, C. J., Watt, F. M. 2018

    Abstract

    Myosins are molecular motors that are well known for their role in cell movement and contractile functions. Although extensively studied in muscle physiology, little is known about the function of myosins in mammalian skin. As part of the Sanger Institute Mouse Genetics Project, we have identified a role for Myo10 in pigmentation, with a phenotype unlike those of Myo5a or Myo7a. Adult mice homozygous for a disrupted Myo10 allele on a C57BL/6N background displayed a high degree of penetrance for white patches on their abdomen and dorsal surface. Forepaw syndactyly and hind paw syndactyly were also observed in these mice. Tail epidermal wholemounts showed a complete lack of melanocytes in the hair follicles and interfollicular epidermis. Myo10 has previously been implicated in human pigmentation. Our current study reveals involvement of Myo10 in murine skin pigmentation.

    View details for DOI 10.1111/exd.13528

    View details for PubMedID 29509981

  • Immunomodulatory role of Keratin 76 in oral and gastric cancer. Nature communications Sequeira, I., Neves, J. F., Carrero, D., Peng, Q., Palasz, N., Liakath-Ali, K., Lord, G. M., Morgan, P. R., Lombardi, G., Watt, F. M. 2018; 9 (1): 3437

    Abstract

    Keratin 76 (Krt76) is expressed in the differentiated epithelial layers of skin, oral cavity and squamous stomach. Krt76 downregulation in human oral squamous cell carcinomas (OSCC) correlates with poor prognosis. We show that genetic ablation of Krt76 in mice leads to spleen and lymph node enlargement, an increase in regulatory T cells (Tregs) and high levels of pro-inflammatory cytokines. Krt76-/- Tregs have increased suppressive ability correlated with increased CD39 and CD73 expression, while their effector T cells are less proliferative than controls. Loss of Krt76 increases carcinogen-induced tumours in tongue and squamous stomach. Carcinogenesis is further increased when Treg levels are elevated experimentally. The carcinogenesis response includes upregulation of pro-inflammatory cytokines and enhanced accumulation of Tregs in the tumour microenvironment. Tregs also accumulate in human OSCC exhibiting Krt76 loss. Our study highlights the role of epithelial cells in modulating carcinogenesis via communication with cells of the immune system.

    View details for PubMedID 30143634

  • cells and acquisition of stem cell properties. Nature cell biology Donati, G., Rognoni, E., Hiratsuka, T., Liakath-Ali, K., Hoste, E., Kar, G., Kayikci, M., Russell, R., Kretzschmar, K., Mulder, K. W., Teichmann, S. A., Watt, F. M. 2017; 19 (6): 603-613

    Abstract

    The epidermis is maintained by multiple stem cell populations whose progeny differentiate along diverse, and spatially distinct, lineages. Here we show that the transcription factor Gata6 controls the identity of the previously uncharacterized sebaceous duct (SD) lineage and identify the Gata6 downstream transcription factor network that specifies a lineage switch between sebocytes and SD cells. During wound healing differentiated Gata6+ cells migrate from the SD into the interfollicular epidermis and dedifferentiate, acquiring the ability to undergo long-term self-renewal and differentiate into a much wider range of epidermal lineages than in undamaged tissue. Our data not only demonstrate that the structural and functional complexity of the junctional zone is regulated by Gata6, but also reveal that dedifferentiation is a previously unrecognized property of post-mitotic, terminally differentiated cells that have lost contact with the basement membrane. This resolves the long-standing debate about the contribution of terminally differentiated cells to epidermal wound repair.

    View details for DOI 10.1038/ncb3532

    View details for PubMedID 28504705

  • A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells NATURE COMMUNICATIONS Walko, G., Woodhouse, S., Pisco, A. O., Rognoni, E., Liakath-Ali, K., Lichtenberger, B. M., Mishra, A., Telerman, S. B., Viswanathan, P., Logtenberg, M., Renz, L. M., Donati, G., Quist, S. R., Watt, F. M. 2017; 8

    Abstract

    Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2.

    View details for DOI 10.1038/ncomms14744

    View details for Web of Science ID 000397110200001

    View details for PubMedID 28332498

    View details for PubMedCentralID PMC5376649

  • Spatial constraints govern competition of mutant clones in human epidermis. Nature communications Lynch, M. D., Lynch, C. N., Craythorne, E., Liakath-Ali, K., Mallipeddi, R., Barker, J. N., Watt, F. M. 2017; 8 (1): 1119

    Abstract

    Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

    View details for DOI 10.1038/s41467-017-00993-8

    View details for PubMedID 29066762

    View details for PubMedCentralID PMC5654977

  • A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis. eLife Mishra, A., Oulès, B., Pisco, A. O., Ly, T., Liakath-Ali, K., Walko, G., Viswanathan, P., Tihy, M., Nijjher, J., Dunn, S. J., Lamond, A. I., Watt, F. M. 2017; 6

    Abstract

    Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here, we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA - promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.

    View details for DOI 10.7554/eLife.27356

    View details for PubMedID 29043977

    View details for PubMedCentralID PMC5667932

  • Pelota Regulates Epidermal Differentiation by Modulating BMP and PI3K/AKT Signaling Pathways JOURNAL OF INVESTIGATIVE DERMATOLOGY Elkenani, M., Nyamsuren, G., Raju, P., Liakath-Ali, K., Hamdaoui, A., Kata, A., Dressel, R., Klonisch, T., Watt, F. M., Engel, W., Thliveris, J. A., Pantakani, D. V., Adham, I. M. 2016; 136 (8): 1664-1671

    Abstract

    The depletion of evolutionarily conserved pelota protein causes impaired differentiation of embryonic and spermatogonial stem cells. In this study, we show that temporal deletion of pelota protein before epidermal barrier acquisition leads to neonatal lethality due to perturbations in permeability barrier formation. Further analysis indicated that this phenotype is a result of failed processing of profilaggrin into filaggrin monomers, which promotes the formation of a protective epidermal layer. Molecular analyses showed that pelota protein negatively regulates the activities of bone morphogenetic protein and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in the epidermis. To address whether elevated activities of bone morphogenetic protein and PI3K/AKT signaling pathways were the cause for the perturbed epidermal barrier in Pelo-deficient mice, we made use of organotypic cultures of skin explants from control and mutant embryos at embryonic day 15.5. Inhibition of PI3K/AKT signaling did not significantly affect the bone morphogenetic protein activity. However, inhibition of bone morphogenetic protein signaling caused a significant attenuation of PI3K/AKT activity in mutant skin and, more interestingly, the restoration of profilaggrin processing and normal epidermal barrier function. Therefore, increased activity of the PI3K/AKT signaling pathway in Pelo-deficient skin might conflict with the dephosphorylation of profilaggrin and thereby affect its proper processing into filaggrin monomers and ultimately the epidermal differentiation.

    View details for DOI 10.1016/j.jid.2016.04.020

    View details for Web of Science ID 000380585200092

    View details for PubMedID 27164299

  • Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure JOURNAL OF PATHOLOGY Liakath-Ali, K., Vancollie, V. E., Lelliott, C. J., Speak, A. O., Lafont, D., Protheroe, H. J., Ingvorsen, C., Galli, A., Green, A., Gleeson, D., Ryder, E., Glover, L., Vizcay-Barrena, G., Karp, N. A., Arends, M. J., Brenn, T., Spiegel, S., Adams, D. J., Watt, F. M., van der Weyden, L. 2016; 239 (3): 374-383

    Abstract

    The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    View details for DOI 10.1002/path.4737

    View details for Web of Science ID 000383594300013

    View details for PubMedID 27126290

    View details for PubMedCentralID PMC4924601

  • Macrophage Infiltration and Alternative Activation during Wound Healing Promote MEK1-Induced Skin Carcinogenesis CANCER RESEARCH Weber, C., Telerman, S. B., Reimer, A. S., Sequeira, I., Liakath-Ali, K., Arwert, E. N., Watt, F. M. 2016; 76 (4): 805-817

    Abstract

    Macrophages are essential for the progression and maintenance of many cancers, but their role during the earliest stages of tumor formation is unclear. To test this, we used a previously described transgenic mouse model of wound-induced skin tumorigenesis, in which expression of constitutively active MEK1 in differentiating epidermal cells results in chronic inflammation (InvEE mice). Upon wounding, the number of epidermal and dermal monocytes and macrophages increased in wild-type and InvEE skin, but the increase was greater, more rapid, and more sustained in InvEE skin. Macrophage ablation reduced tumor incidence. Furthermore, bioluminescent imaging in live mice to monitor macrophage flux at wound sites revealed that macrophage accumulation was predictive of tumor formation; wounds with the greatest number of macrophages at day 5 went on to develop tumors. Gene expression profiling of flow-sorted monocytes, macrophages, and T cells from InvEE and wild-type skin showed that as wound healing progressed, InvEE macrophages altered their phenotype. Throughout wound healing and after wound closure, InvEE macrophages demonstrated sustained upregulation of several markers implicated in alternative macrophage activation including arginase-1 (ARG1) and mannose receptor (CD206). Notably, inhibition of ARG1 activity significantly reduced tumor formation and epidermal proliferation in vivo, whereas addition of L-arginase to cultured keratinocytes stimulated proliferation. We conclude that macrophages play a key role in early, inflammation-mediated skin tumorigenesis, with mechanistic evidence suggesting that ARG1 secretion drives tumor development by stimulating epidermal cell proliferation. These findings highlight the importance of cancer immunotherapies aiming to polarize tumor-associated macrophages toward an antitumor phenotype.

    View details for DOI 10.1158/0008-5472.CAN-14-3676

    View details for Web of Science ID 000370129600007

    View details for PubMedID 26754935

    View details for PubMedCentralID PMC4757739

  • Mimicking the topography of the epidermal-dermal interface with elastomer substrates INTEGRATIVE BIOLOGY Viswanathan, P., Guvendiren, M., Chua, W., Telerman, S. B., Liakath-Ali, K., Burdick, J. A., Watt, F. M. 2016; 8 (1): 21-29

    Abstract

    In human skin the interface between the epidermis and dermis is not flat, but undulates. The dimensions of the undulations change as a function of age and disease. Epidermal stem cell clusters lie in specific locations relative to the undulations; however, whether their location affects their properties is unknown. To explore this, we developed a two-step protocol to create patterned substrates that mimic the topographical features of the human epidermal-dermal interface. Substrates with negative patterns were first fabricated by exposing a photocurable formulation to light, controlling the topographical features (such as diameter, height and center-to-center distance) by the photomask pattern dimensions and UV crosslinking time. The negative pattern was then translated to PDMS elastomer to fabricate substrates with 8 unique surface topographies on which primary human keratinocytes were cultured. We found that cells were patterned according to topography, and that separate cues determined the locations of stem cells, differentiated cells and proliferating cells. The biomimetic platform we have developed will be useful for probing the effect of topography on stem cell behaviour.

    View details for DOI 10.1039/c5ib00238a

    View details for Web of Science ID 000368348900003

    View details for PubMedID 26658424

  • Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse OPEN BIOLOGY Coelho, P. A., Bury, L., Shahbazi, M. N., Liakath-Ali, K., Tate, P. H., Wormald, S., Hindley, C. J., Huch, M., Archer, J., Skarnes, W. C., Zernicka-Goetz, M., Glover, D. M. 2015; 5 (12)

    Abstract

    To address the long-known relationship between supernumerary centrosomes and cancer, we have generated a transgenic mouse that permits inducible expression of the master regulator of centriole duplication, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 from this transgene advances the onset of tumour formation that occurs in the absence of the tumour suppressor p53. Plk4 over-expression also leads to hyperproliferation of cells in the pancreas and skin that is enhanced in a p53 null background. Pancreatic islets become enlarged following Plk4 over-expression as a result of equal expansion of α- and β-cells, which exhibit centrosome amplification. Mice overexpressing Plk4 develop grey hair due to a loss of differentiated melanocytes and bald patches of skin associated with a thickening of the epidermis. This reflects an increase in proliferating cells expressing keratin 5 in the basal epidermal layer and the expansion of these cells into suprabasal layers. Such cells also express keratin 6, a marker for hyperplasia. This is paralleled by a decreased expression of later differentiation markers, involucrin, filaggrin and loricrin. Proliferating cells showed an increase in centrosome number and a loss of primary cilia, events that were mirrored in primary cultures of keratinocytes established from these animals. We discuss how repeated duplication of centrioles appears to prevent the formation of basal bodies leading to loss of primary cilia, disruption of signalling and thereby aberrant differentiation of cells within the epidermis. The absence of p53 permits cells with increased centrosomes to continue dividing, thus setting up a neoplastic state of error prone mitoses, a prerequisite for cancer development.

    View details for DOI 10.1098/rsob.150209

    View details for Web of Science ID 000367482100009

    View details for PubMedID 26701933

    View details for PubMedCentralID PMC4703062

  • Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen NATURE COMMUNICATIONS Liakath-Ali, K., Vancollie, V. E., Heath, E., Smedley, D. P., Estabel, J., Sunter, D., DiTommaso, T., White, J. K., Ramirez-Solis, R., Smyth, I., Steel, K. P., Watt, F. M. 2014; 5

    Abstract

    Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community.

    View details for DOI 10.1038/ncomms4540

    View details for Web of Science ID 000335219300003

    View details for PubMedID 24721909

    View details for PubMedCentralID PMC3996542

  • Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes CELL White, J. K., Gerdin, A., Karp, N. A., Ryder, E., Buljan, M., Bussell, J. N., Salisbury, J., Clare, S., Ingham, N. J., Podrini, C., Houghton, R., Estabel, J., Bottomley, J. R., Melvin, D. G., Sunter, D., Adams, N. C., Tannahill, D., Logan, D. W., MacArthur, D. G., Flint, J., Mahajan, V. B., Tsang, S. H., Smyth, I., Watt, F. M., Skarnes, W. C., Dougan, G., Adams, D. J., Ramirez-Solis, R., Bradley, A., Steel, K. P. 2013; 154 (2): 452-464

    Abstract

    Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PAPERCLIP:

    View details for DOI 10.1016/j.cell.2013.06.022

    View details for Web of Science ID 000321950700020

    View details for PubMedID 23870131

    View details for PubMedCentralID PMC3717207

  • MeCP2(270) Mutant Protein Is Expressed in Astrocytes as well as in Neurons and Localizes in the Nucleus CYTOGENETIC AND GENOME RESEARCH Kifayathullah, L. A., Arunachalam, J. P., Bodda, C., Agbemenyah, H. Y., Laccone, F. A., Mannan, A. U. 2010; 129 (4): 290-297

    Abstract

    The MECP2 gene, located at Xq28, encodes methyl-CpG-binding protein 2 (MeCP2), which is frequently mutated (up to 90%) in Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder, which affects primarily girls during early childhood and it is one of the most common causes of mental retardation in females. R270X is one of the most frequent recurrent MECP2 mutations among RTT cohorts. The R270X mutation resides within the TRD-NLS (Transcription Repression Domain-Nuclear Localization Signal) region of MeCP2 and causes a more severe clinical phenotype with increased mortality as compared to other mutations. To evaluate the functional role of the R270X mutation, we generated a transgenic mouse model expressing MeCP2(270_EGFP) (human mutation equivalent) by BAC recombineering. The expression pattern of MeCP2(270_EGFP) was similar to that of endogenous MeCP2. Strikingly, MeCP2(270_EGFP) localizes in the nucleus, contrary to the conjecture that R270X could cause disruption of the NLS. In primary hippocampal cells, we show that MeCP2(270_EGFP) was expressed in astrocytes by colocalization with the astrocyte-specific marker glial fibrillary acidic protein. Our data showing expression of MeCP2(270_EGFP) in transgenic mice astrocytes further reinforce the recent findings concerning the expression of MeCP2 in the glial cells.

    View details for DOI 10.1159/000315906

    View details for Web of Science ID 000280683800005

    View details for PubMedID 20625242

  • Microsatellite markers for the Indian golden silkmoth, Antheraea assama (Saturniidae: Lepidoptera) MOLECULAR ECOLOGY RESOURCES Arunkumar, K. P., Kifayathullah, L., Nagaraju, J. 2009; 9 (1): 268-270

    Abstract

    Antheraea assama, an economically important and scientifically unexplored Indian wild silkmoth, is unique among saturniid moths. For this species, a total of 87 microsatellite markers was derived from 35 000 expressed sequence tags and a microsatellite-enriched sub-genomic library. Forty individuals collected from Tura and West Garo Hills region of Northeast India were screened for each of these loci. Ten loci from expressed sequence tags and one from genomic library were found to be polymorphic. These microsatellite markers will be useful resources for population genetic studies of A. assama and other closely related species of saturniids. This is the first report on development of microsatellite markers for any saturniid species.

    View details for DOI 10.1111/j.1755-0998.2008.02414.x

    View details for Web of Science ID 000262678900064

    View details for PubMedID 21564623