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) and postdoctoral/principal investigator grant from the Larry L Hillblom Foundation.

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 the 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, awarded by King's College London, UK.

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 & Hillblom Fellow, working under the mentorship of Professor Thomas Südhof at Stanford on genetic mechanisms involved in synapse formation and function. He is also an avid communicator of science, eLife Community Ambassador, STEM Ambassador and Ambassador for open science, research rigor and reproducibility.

Academic Appointments


Honors & Awards


  • Fellow of the Academy for Future Leaders in Dermatology, European Society for Dermatological Research (October 2019)
  • Hillblom Research Fellowship (long-term), Larry L Hillblom Foundation, California, USA (July 2020-July 2023)
  • EMBO Long-Term Fellowship, European Molecular Biology Organisation (EMBO) (July 2018 - July 2020)
  • RaRe (Rigor and Reproducibility) Researcher Award, Stanford Program on Research Rigor & Reproducibility, Stanford University (January 2024)
  • Star Mentor, Stanford Bio-X (December 2021)
  • 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)

All Publications


  • Editorial: Alternative splicing in brain function. Frontiers in molecular neuroscience Liakath-Ali, K., Soller, M. 2023; 16: 1335549

    View details for DOI 10.3389/fnmol.2023.1335549

    View details for PubMedID 38076210

    View details for PubMedCentralID PMC10702566

  • Distinct neurexin-cerebellin complexes control AMPAand NMDA-receptor responses in a circuit-dependent manner (vol 12, e94305, 2022) ELIFE Dai, J., Liakath-Ali, K., Golf, S., Sudhof, T. C. 2023; 12

    View details for DOI 10.7554/eLife.94305

    View details for Web of Science ID 001115198100001

    View details for PubMedID 37943030

    View details for PubMedCentralID PMC10635641

  • Distinct neurexin-cerebellin complexes control AMPA- and NMDA-receptor responses in a circuit-dependent manner. eLife Dai, J., Liakath-Ali, K., Golf, S. R., Sudhof, T. C. 2022; 11

    Abstract

    At CA1subiculum synapses, alternatively spliced neurexin-1 (Nrxn1SS4+) and neurexin-3 (Nrxn3SS4+) enhance NMDA-receptors and suppress AMPA-receptors, respectively, without affecting synapse formation. Nrxn1SS4+ and Nrxn3SS4+ act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1 receptors. Whether neurexin-Cbln2-GluD1 signaling has additional functions besides regulating NMDA- and AMPA-receptors, and whether such signaling performs similar roles at other synapses, however, remains unknown. Here, we demonstrate using constitutive Cbln2 deletions in mice that at CA1subiculum synapses, Cbln2 performs no additional developmental roles besides regulating AMPA- and NMDA-receptors. Moreover, low-level expression of functionally redundant Cbln1 did not compensate for a possible synapse-formation function of Cbln2 at CA1subiculum synapses. In exploring the generality of these findings, we examined the prefrontal cortex where Cbln2 was recently implicated in spinogenesis, and the cerebellum where Cbln1 is known to regulate parallel-fiber synapses. In the prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively controlled NMDA-receptors without affecting spine or synapse numbers, whereas Nrxn3SS4+-Cbln2 signaling had no apparent role. In the cerebellum, conversely, Nrxn3SS4+-Cbln1 signaling regulated AMPA-receptors, whereas now Nrxn1SS4+-Cbln1 signaling had no manifest effect. Thus, Nrxn1SS4+- and Nrxn3SS4+-Cbln1/2 signaling complexes differentially control NMDA- and AMPA-receptors in different synapses in diverse neural circuits without regulating synapse or spine formation.

    View details for DOI 10.7554/eLife.78649

    View details for PubMedID 36205393

  • Embigin is a fibronectin receptor that affects sebaceous gland differentiation and metabolism. Developmental cell Sipila, K., Rognoni, E., Jokinen, J., Tewary, M., Vietri Rudan, M., Talvi, S., Jokinen, V., Dahlstrom, K. M., Liakath-Ali, K., Mobasseri, A., Du-Harpur, X., Kapyla, J., Nutt, S. L., Salminen, T. A., Heino, J., Watt, F. M. 2022

    Abstract

    Stem cell renewal and differentiation are regulated by interactions with the niche. Although multiple cell populations have been identified in distinct anatomical compartments, little is known about niche-specific molecular factors. Using skin as a model system and combining single-cell RNA-seq data analysis, immunofluorescence, and transgenic mouse models, we show that the transmembrane protein embigin is specifically expressed in the sebaceous gland and that the number of embigin-expressing cells is negatively regulated by Wnt. The loss of embigin promotes exit from the progenitor compartment and progression toward differentiation, and also compromises lipid metabolism. Embigin modulates sebaceous niche architecture by affecting extracellular matrix organization and basolateral targeting of monocarboxylate transport. We discover through ligand screening that embigin is a direct fibronectin receptor, binding to the N-terminal fibronectin domain without impairing integrin function. Our results solve the long-standing question of how embigin regulates cell adhesion and demonstrate a mechanism that couples adhesion and metabolism.

    View details for DOI 10.1016/j.devcel.2022.05.011

    View details for PubMedID 35671757

  • Transsynaptic cerebellin 4-neogenin 1 signaling mediates LTP in the mouse dentate gyrus. Proceedings of the National Academy of Sciences of the United States of America Liakath-Ali, K., Polepalli, J. S., Lee, S. J., Cloutier, J. F., Südhof, T. C. 2022; 119 (20): e2123421119

    Abstract

    SignificanceSynapses are controlled by transsynaptic adhesion complexes that mediate bidirectional signaling between pre- and postsynaptic compartments. Long-term potentiation (LTP) of synaptic transmission is thought to enable synaptic modifications during memory formation, but the signaling mechanisms involved remain poorly understood. We show that binding of cerebellin-4 (Cbln4), a secreted ligand of presynaptic neurexin adhesion molecules, to neogenin-1, a postsynaptic surface protein known as a developmental netrin receptor, is essential for normal LTP at entorhinal cortex→dentate gyrus synapses in mice. Cbln4 and neogenin-1 are dispensable for basal synaptic transmission and not involved in establishing synaptic connections as such. Our data identify a netrin receptor as a postsynaptic organizer of synaptic plasticity that collaborates specifically with the presynaptic neurexin-ligand Cbln4.

    View details for DOI 10.1073/pnas.2123421119

    View details for PubMedID 35544694

  • Teneurins assemble into presynaptic nanoclusters that promote synapse formation via postsynaptic non-teneurin ligands. Nature communications Zhang, X., Lin, P., Liakath-Ali, K., Sudhof, T. C. 2022; 13 (1): 2297

    Abstract

    Extensive studies concluded that homophilic interactions between pre- and postsynaptic teneurins, evolutionarily conserved cell-adhesion molecules, encode the specificity of synaptic connections. However, no direct evidence is available to demonstrate that teneurins are actually required on both pre- and postsynaptic neurons for establishing synaptic connections, nor is it known whether teneurins are localized to synapses. Using super-resolution microscopy, we demonstrate that Teneurin-3 assembles into presynaptic nanoclusters of approximately 80nm in most excitatory synapses of the hippocampus. Presynaptic deletions of Teneurin-3 and Teneurin-4 in the medial entorhinal cortex revealed that they are required for assembly of entorhinal cortex-CA1, entorhinal cortex-subiculum, and entorhinal cortex-dentate gyrus synapses. Postsynaptic deletions of teneurins in the CA1 region, however, had no effect on synaptic connectionsfrom any presynaptic input. Our data suggest that different from the current prevailing view, teneurins promote the establishment of synaptic connections exclusively as presynaptic cell-adhesion molecules, most likely via their nanomolar-affinity binding to postsynaptic latrophilins.

    View details for DOI 10.1038/s41467-022-29751-1

    View details for PubMedID 35484136

  • Calsyntenin-3, an atypical cadherin, suppresses inhibitory synapses but increases excitatory parallel-fiber synapses in cerebellum. eLife Liu, Z., Jiang, M., Liakath-Ali, K., Sclip, A., Ko, J., Zhang, R. S., Sudhof, T. C. 2022; 11

    Abstract

    Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic kinesin adaptors in vesicular transport. Here, we show that, surprisingly, acute CRISPR-mediated deletion of calsyntenin-3 in mouse cerebellum in vivo causes a large decrease in inhibitory synapse, but a robust increase in excitatory parallel-fiber synapses in Purkinje cells. As a result, inhibitory synaptic transmission was suppressed, whereas parallel-fiber synaptic transmission was enhanced in Purkinje cells by the calsyntenin-3 deletion. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Sparse selective deletion of calsyntenin-3 only in Purkinje cells recapitulated the synaptic phenotype, indicating that calsyntenin-3 acts by a cell-autonomous postsynaptic mechanism in cerebellum. Thus, by promoting formation of excitatory parallel-fiber synapses and decreasing formation of inhibitory synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells.

    View details for DOI 10.7554/eLife.70664

    View details for PubMedID 35420982

  • Molecular self-avoidance in synaptic neurexin complexes. Science advances Wang, C. Y., Trotter, J. H., Liakath-Ali, K., Lee, S., Liu, X., Sudhof, T. C. 1800; 7 (51): eabk1924

    Abstract

    [Figure: see text].

    View details for DOI 10.1126/sciadv.abk1924

    View details for PubMedID 34919427

  • Translational control of stem cell function. Nature reviews. Molecular cell biology Saba, J. A., Liakath-Ali, K., Green, R., Watt, F. M. 2021

    Abstract

    Stem cells are characterized by their ability to self-renew and differentiate into many different cell types. Research has focused primarily on how these processes are regulated at a transcriptional level. However, recent studies have indicated that stem cell behaviour is strongly coupled to the regulation of protein synthesis by the ribosome. In this Review, we discuss how different translation mechanisms control the function of adult and embryonic stem cells. Stem cells are characterized by low global translation rates despite high levels of ribosome biogenesis. The maintenance of pluripotency, the commitment to a specific cell fate and the switch to cell differentiation depend on the tight regulation of protein synthesis and ribosome biogenesis. Translation regulatory mechanisms that impact on stem cell function include mTOR signalling, ribosome levels, and mRNA and tRNA features and amounts. Understanding these mechanisms important for stem cell self-renewal and differentiation may also guide our understanding of cancer grade and metastasis.

    View details for DOI 10.1038/s41580-021-00386-2

    View details for PubMedID 34272502

  • GluD1 is a signal transduction device disguised as an ionotropic receptor NATURE Dai, J., Patzke, C., Liakath-Ali, K., Seigneur, E., Sudhof, T. C. 2021

    Abstract

    Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins1-4. It is unclear whether neurexin-cerebellin-GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1-cerebellin-2 and neurexin-3-cerebellin-2 complexes differentially regulate NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-35,6 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5-13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin-cerebellin signals into postsynaptic receptor responses.

    View details for DOI 10.1038/s41586-021-03661-6

    View details for Web of Science ID 000662164200002

    View details for PubMedID 34135511

  • The Perils of Navigating Activity-Dependent Alternative Splicing of Neurexins FRONTIERS IN MOLECULAR NEUROSCIENCE Liakath-Ali, K., Sudhof, T. C. 2021; 14: 659681

    Abstract

    Neurexins are presynaptic cell-adhesion molecules essential for synaptic function that are expressed in thousands of alternatively spliced isoforms. Recent studies suggested that alternative splicing at splice site 4 (SS4) of Nrxn1 is tightly regulated by an activity-dependent mechanism. Given that Nrxn1 alternative splicing at SS4 controls NMDA-receptor-mediated synaptic responses, activity-dependent SS4 alternative splicing would suggest a new synaptic plasticity mechanism. However, conflicting results confound the assessment of neurexin alternative splicing, prompting us to re-evaluate this issue. We find that in cortical cultures, membrane depolarization by elevated extracellular K+-concentrations produced an apparent shift in Nrxn1-SS4 alternative splicing by inducing neuronal but not astroglial cell death, resulting in persistent astroglial Nrxn1-SS4+ expression and decreased neuronal Nrxn1-SS4- expression. in vivo, systemic kainate-induced activation of neurons in the hippocampus produced no changes in Nrxn1-SS4 alternative splicing. Moreover, focal kainate injections into the mouse cerebellum induced small changes in Nrxn1-SS4 alternative splicing that, however, were associated with large decreases in Nrxn1 expression and widespread DNA damage. Our results suggest that although Nrxn1-SS4 alternative splicing may represent a mechanism of activity-dependent synaptic plasticity, common procedures for testing this hypothesis are prone to artifacts, and more sophisticated approaches will be necessary to test this important question.

    View details for DOI 10.3389/fnmol.2021.659681

    View details for Web of Science ID 000631420600001

    View details for PubMedID 33767611

    View details for PubMedCentralID PMC7985251

  • Latrophilin-2 and latrophilin-3 are redundantly essential for parallel-fiber synapse function in cerebellum. eLife Zhang, R. S., Liakath-Ali, K., Sudhof, T. C. 2020; 9

    Abstract

    Latrophilin-2 (Lphn2) and latrophilin-3 (Lphn3) are adhesion GPCRs that serve as postsynaptic recognition molecules in CA1 pyramidal neurons of the hippocampus, where they are localized to distinct dendritic domains and are essential for different sets of excitatory synapses. Here, we studied Lphn2 and Lphn3 in the cerebellum. We show that latrophilins are abundantly and differentially expressed in the cerebellar cortex. Using conditional KO mice, we demonstrate that the Lphn2/3 double-deletion but not the deletion of Lphn2 or Lphn3 alone suppresses parallel-fiber synapses and reduces parallel-fiber synaptic transmission by ~50% without altering release probability. Climbing-fiber synapses, conversely, were unaffected. Even though ~50% of total cerebellar Lphn3 protein is expressed in Bergmann glia, Lphn3 deletion from Bergmann glia did not detectably impair excitatory or inhibitory synaptic transmission. Our studies demonstrate that Lphn2 and Lphn3 are selectively but redundantly required in Purkinje cells for parallel-fiber synapses.

    View details for DOI 10.7554/eLife.54443

    View details for PubMedID 32202499

  • The phosphatase regulator NIPP1 restrains chemokine-driven skin inflammation. The Journal of investigative dermatology Verbinnen, I., Jonkhout, M., Liakath-Ali, K., Szekér, K., Ferreira, M., Boens, S., Rouget, R., Nikolic, M., Schlenner, S., Van Eynde, A., Bollen, M. 2020

    Abstract

    NIPP1 is a ubiquitously expressed nuclear protein that regulates functions of protein Ser/Thr phosphatase-1 in cell proliferation and lineage specification. The role of NIPP1 in tissue homeostasis is not fully understood. Here we show that the selective deletion of NIPP1 in mouse epidermis resulted in epidermal hyperproliferation, a reduced adherence of basal keratinocytes and a gradual decrease in the stemness of hair follicle stem cells, culminating in hair loss. This complex phenotype was associated with chronic sterile skin inflammation and could be partially rescued by dexamethasone treatment. NIPP1-deficient keratinocytes massively expressed pro-inflammatory chemokines and immunomodulatory proteins in a cell-autonomous manner. Chemokines subsequently induced the recruitment and activation of immune cells, in particular conventional dendritic cells and Langerhans cells, accounting for the chronic inflammation phenotype. Our data identify NIPP1 as a key regulator of epidermal homeostasis and as a potential target for the treatment of inflammatory skin diseases.

    View details for DOI 10.1016/j.jid.2020.01.008

    View details for PubMedID 31972250

  • 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. n., Neves, J. F., Carrero, D. n., Peng, Q. n., Palasz, N. n., Liakath-Ali, K. n., Lord, G. M., Morgan, P. R., Lombardi, G. n., 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

  • 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

  • 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

  • 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