Institute of Medical Biology (IMB), A*STAR

Research

Epithelial Biology

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birgit.lane@sris.a-star.edu.sg

Birgit Lane

As IMB's first Executive Director, Birgit Lane oversaw the Institute's creation in 2007 from her previous position as Executive Director of its forerunner, the Centre for Molecular Medicine. She first joined CMM on coming to Singapore in January 2005, on sabbatical leave from the University of Dundee. Previously she held the Cox Chair of Anatomy and Cell Biology in the College of Life Sciences at Dundee from 1991 until her resignation in 2009. Birgit began her interests in epithelial biology with her BSc and PhD degrees in Zoology at University College London; she worked as a postdoctoral scientist at UCL, Imperial College London and Cold Spring Harbor Laboratory, New York before joining ICRF (now Cancer Research UK) in 1980, where she subsequently became a tenured staff member. In 1990 she moved her group from ICRF Clare Hall to the University of Dundee, to establish the CRUK Laboratories at Dundee, together with her husband David Lane and also David Glover.

Birgit Lane has published over 200 research papers and reviews. She is known internationally for her work on keratins and has a long-standing interest in the function of the keratin cytoskeleton in epithelia and its importance in disease. She has made pioneering contributions to the use of monoclonal antibodies to keratins in diagnostic pathology and cell biology, and to the recognition of keratin mutations as causing inherited skin fragility disorders.

In Singapore, Professor Birgit Lane also holds adjunct appointments in A*STAR's IMCB and in the Departments of Pathology and Biochemistry at NUS, and is an Honorary Visiting Consultant at the National Skin Centre. She also is an Adjunct Professor at the Karolinska Institute, Sweden and Emeritus Professor at the University of Dundee. She is an elected Fellow of the Royal Society of Edinburgh and of the UK's Academy of Medical Sciences.

Epithelial cells grow as sheets, covering our bodies and lining the spaces and organs inside. These cells are incredibly strong due to their internal keratin filament networks. Mutations in keratins lead to fragile skin (EBS, or "butterfly children"). Working with dermatologists, this research group studies the far ranging pathological consequences of keratin mutations - from cell stress to potential cancer susceptibility - to see how these diseases can best be identified and their severity reduced.

Keratin filament proteins of the cytoskeleton play an important part in promoting, defining and maintaining epithelial differentiation and function. Epithelia are sealed sheets of polarised cells that line spaces and enclose organs and maintain large functional differences across the sheet. Keratin filament protein networks cross the cytoplasm of epithelial cells, link into anchorage junctions around the edges and providing the physical resilience for epithelial tissues to withstand normal wear and tear. Mutations in keratins lead to inherited tissue fragility disorders such as EBS, and recent data from this lab and others suggest that part of this fragility arises from the stress signals originating from mutant protein accumulating in cells.

Epithelial cells sense mechanical stress in many natural situations. Tissue stretching occurs normally in bladder and lungs, and more slowly in growth or development; upon ischemia, mechanical stress arises from hypotonic cell swelling. How do cells sense, resist and respond to such mechanical changes? The keratin filament system is well placed to relay changes in tissue tension that impact on cell behaviour in development, growth, wound healing and cancer. We collaborate with clinicians and engineers to stress cells and analyse their response, looking for points at which intervention can provide new targets for disease therapies.

Current projects in the lab include (i) mechanical signaling in keratinocyte wound activation; (ii) therapeutic strategies for keratin disorders; (iii) susceptibilities to non-melanoma skin cancer; (iv) post-translational regulation of keratin filament proteins; (v) genetic mechanisms underlying skin disorders. The lab has also established a renowned knowledgebase, the Human Intermediate Filament Database.

Group Members

Senior Research Scientists	Ildiko Szeverenyi
	Chidambaram Natesavelalar
Senior Research Manager	Declan Lunny
Research Clinicians	Huang Jingxiang
Research Fellows	Tan Tong San
	Ng Yi Zhen
	Woo Sin Tung, Vivien
Postgraduate students	Hideki Itoh (ARAP)
	Giorgiana Salgado (SINGA)
	Chen Shi-Min, Cheryl
Senior Research Officer	Koh Mei Ling, Rosita
Research Officers	Muhammed Jasrie Firadaus
Laboratory Support Officer	Periyathambi Singaravelu, Tamil Selvan

Kumar D, Puan KJ, Andiappan AK, Lee B, Westerlaken GH, Haase D, Melchiotti R, Li Z, Yusof N, Lum J, Koh G, Foo S, Yeong J, Alves AC, Pekkanen J, Sun LD, Irwanto A, Fairfax BP, Naranbhai V, Common JE, Tang M, Chuang CK, Jarvelin MR, Knight JC, Zhang X, Chew FT, Prabhakar S, Jianjun L, Wang Y, Zolezzi F, Poidinger M, Lane EB, Meyaard L, Rötzschke O. A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus. Genome Med. 2017 Feb 20;9(1):18. doi: 10.1186/s13073-017-0404-6 Link

Kriszt R, Arai S, Itoh H, Lee MH, Goralczyk AG, Ang XM, Cypess AM, White AP, Shamsi F, Xue R, Lee JY, Lee SC, Hou Y, Kitaguchi T, Sudhaharan T, Ishiwata S, Lane EB, Chang YT, Tseng YH, Suzuki M, Raghunath M. Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes. Sci Rep. 2017 May 3;7(1):1383. doi: 10.1038/s41598-017-00291-9 Link

Badowski C, Sim AYL, Verma C, Szeverényi I, Natesavelalar C, Terron-Kwiatkowski A, Harper J, O'Toole EA, Lane EB. Modeling the Structure of Keratin 1 and 10 Terminal Domains and their Misassembly in Keratoderma. J Invest Dermatol. 2017 Sep;137(9):1914-1923. doi: 10.1016/j.jid.2017.03.038 Link

Zupancic T, Sersa G, Törmä H, Lane EB, Herrmann H, Komel R, Liovic M. Keratin gene mutations influence the keratinocyte response to DNA damage and cytokine induced apoptosis. Arch Dermatol Res. 2017 Jun 24. doi: 10.1007/s00403-017-1757-9 Link

Sundaram GM, Ismail HM, Bashir M, Muhuri M, Vaz C, Nama S, Ow GS, Vladimirovna IA, Ramalingam R, Burke B, Tanavde V, Kuznetsov V, Lane EB, Sampath P. EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis. J Exp Med. 2017 Oct 2;214(10):2889-2900. doi: 10.1084/jem.20170354 Link

Wong XFCC, Denil SLIJ, Foo JN, Chen H, Tay ASL, Haines RL, Tang MBY, McLean WHI, Sandilands A, Smith FJD, Lane EB, Liu J, Common JEA. Array-based sequencing of filaggrin gene for comprehensive detection of disease-associated variants. J Allergy Clin Immunol. 2017 Oct 19. pii: S0091-6749(17)31588-9. doi: 10.1016/j.jaci.2017.10.001. Link

Itoh H, Arai S, Sudhaharan T, Lee SC, Chang YT, Ishiwata S, Suzuki M and Lane EB. Direct organelle thermometry with fluorescence lifetime imaging microscopy in single myotubes. Chem. Commun. (2016) DOI: 10.1039/C5CC09943A Link

Tan TS, Ng YZ, Badowski C, Dang T, Common JE, Lacina L, Szeverényi I, Lane EB. Assays to Study Consequences of Cytoplasmic Intermediate Filament Mutations: The Case of Epidermal Keratins. Methods Enzymol. 2016;568:219-53. doi: 10.1016/bs.mie.2015.09.030 Link

Kern Rei Chng, Angeline Su Ling Tay, Chenhao Li, Amanda Hui Qi Ng, Jingjing Wang, Bani Kaur Suri, Sri Anusha Matta, Naomi McGovern, Baptiste Janela, Xuan Fei Colin C. Wong, Yang Yie Sio, Bijin Veonice Au, Andreas Wilm, Paola Florez De Sessions, Thiam Chye Lim, Mark Boon Yang Tang, Florent Ginhoux, John E. Connolly, E. Birgitte Lane, Fook Tim Chew, John E. A. Common & Niranjan Nagarajan. Whole metagenome profiling reveals skin microbiome-dependent susceptibility to atopic dermatitis flare. Nature Microbiology 2016;1:16106. doi:10.1038/nmicrobiol.2016.106 Link

Benny P1, Badowski C, Lane B, Raghunath M. “Making more matrix: Enhancing the deposition of dermal-epidermal junction components in vitro and accelerating organotypic skin culture development, using macromolecular crowding.” Tissue Eng Part A. 2015 Jan;21(1-2):183-92. doi: 10.1089/ten.TEA.2013.0784.

Ma D, Chua AW, Yang E, Teo P, Ting Y, Song C, Lane EB, Lee ST. “Breast cancer resistance protein identifies clonogenic keratinocytes in human interfollicular epidermis.” Stem Cell Res Ther. 2015 Mar 24;6:43. doi: 10.1186/s13287-015-0032-2

Oyama K, Arai T, Isaka A, Sekiguchi T, Itoh H, Seto Y, Miyazaki M, Itabashi T, Ohki T, Suzuki M, Ishiwata S. “Directional bleb formation in spherical cells under temperature gradient.” Biophys J. 2015 Jul 21;109(2):355-64. doi: 10.1016/j.bpj.2015.06.016.

Zupancic T, Stojan J, Lane EB, Komel R, Bedina-Zavec A, Liovic M. (2014) “Intestinal cell barrier function in vitro is severely compromised by keratin 8 and 18 mutations identified in patients with inflammatory bowel disease.” PLoS One 9(6): e99398. doi: 10.1371/journal.pone.0099398.

Tan KKB, Salgado G, Connolly J, Chan JKY, Lane EB. “Characterization of fetal keratinocytes, showing enhanced stem cell-like properties: A potential source of cells for skin reconstruction.” Stem Cell Reports 3(2):324-38. doi: 10.1016/j.stemcr.2014.06.005.

Hideki Itoh, Kotaro Oyama, Madoka Suzuki, Shin’ichi Ishiwata. “Microscopic heat pulse-induced calcium dynamics in single WI-38 fibroblasts.” Biophysics Vol. 10, pp. 109–119 (2014) doi: 10.2142/biophysics.10.109

Andiappan AK, Foo JN, Choy MW, Chen H, Common JE, Tang MB, van Bever HP, Giam YC, Suri BK, Ramani A, Nilkanth PP, Lane EB, Wang DY, Chew FT, Liu J. (2012) Validation of GWAS Loci for Atopic Dermatitis in a Singapore Chinese Population. J Invest Dermatol. doi: 10.1038/jid.2011.471. [Epub ahead of print] PMID: 22318392 Link

Cai SC, Chen H, Koh WP, Common JE, van Bever HP, McLean WH, Lane EB, Giam YC, Tang MB. (2011) Filaggrin Mutations are Associated with Recurrent Skin Infection in Singaporean Chinese Patients with Atopic Dermatitis. Br J Dermatol. doi: 10.1111/j.1365-2133.2011.10541.x. [Epub ahead of print] PMID: 21790526 Link

Canning CA, Chan JS, Common JE, Lane EB, Jones CM. (2011) Developmental expression of the fermitin/kindlin gene family in Xenopus laevis embryos. Dev Dyn. 240(8):1958-63. doi: 10.1002/dvdy.22683. Link

Chen H, Common JE, Haines RL, Balakrishnan A, Brown SJ, Goh CS, Cordell HJ, Sandilands A, Campbell LE, Kroboth K, Irvine AD, Goh DL, Tang MB, van Bever HP, Giam YC, McLean WH, Lane EB. (2011) Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations. Br J Dermatol. 165(1):106-114. doi: 10.1111/j.1365-2133.2011.10331.x. PMID: 21428977 Link

Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJ, Moore CB, McLean WH. (2011) Development of Allele-Specific Therapeutic siRNA for Keratin 5 Mutations in Epidermolysis Bullosa Simplex. J Invest Dermatol. Jun 30. [Epub ahead of print] PMID: 21716320 Link

Goudie DR, D’Alessandro M, Merriman B, Lee H, Szeverenyi I, Avery S, O’Connor BD, Nelson SF, Coats SE., Stewart A, Christie L, Pichert G, Friedel J, Hayes I, Burrows N, Whittaker S, Geredes AM, Broesby-Oslen S, Ferguson-Smith MA, Verma C, Lunny DP, Reversade B, Lane EB (2011) Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nat Genetics 43(4):365-9. PMID: 21358634 Link

D’Alessandro M, Coats SE, Jonkman MF, Leigh IM, Lane EB. (2011) Keratin 14-Null Cells a Model to Test the Efficacy of Gene Therapy Approaches in Epithelial Cells. J Invest Dermatol. 131(7):1412-9. PMID: 21326298 Link

Common JE, Brown SJ, Haines RL, Goh CS, Chen H, Balakrishnan A, Munro CS, Tan AW, Tan HH, Tang MB, Lane EB. (2011) Filaggrin Null Mutations Are Not a Protective Factor for Acne Vulgaris. J Invest Dermatol. 2011 Jun;131(6):1378-80. Epub 2011 Feb 17. PMID: 21326297 Link

O'Regan GM, Kemperman PM, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, Puppels GJ, McLean WH, Caspers PJ, Irvine AD. (2010). Raman profiles of the stratum corneum define 3 filaggrin genotype-determined atopic dermatitis endophenotypes. J Allergy Clin Immunol. 126:574-80.e1. PMID: 20621340 Link

Chong KL, Common JE, Lane EB, Goh BK. (2010). A novel mutation in the kinase domain of KIT in an Indian family with a mild piebaldism phenotype. J Dermatol Sci. 59(3):206-9. Epub 2010 Jul 8. PMID: 20688482 Link

Russell D, Ross H, Lane EB. (2010). ERK involvement in resistance to apoptosis in keratinocytes with mutant keratin. J Invest Dermatol. 130:671-81. Epub 2009 Oct 22. PMID: 19847192 Link

Wilson NJ, Messenger AG, Leachman SA, O'Toole EA, Lane EB, McLean WH, Smith FJ. (2010). Keratin K6c Mutations Cause Focal Palmoplantar Keratoderma. J Invest Dermatol. 130: 425-9. PMID: 19609311 Link

Neoh CY, Chen H, Ng SK, Lane EB, Common JE. (2009). A rare connexin 26 mutation in a patient with a forme fruste of keratitis-ichthyosis-deafness (KID) syndrome. Int J Dermatol. 48:1078-81. PMID: 19785089 Link

Liovic M, D'Alessandro M, Tomic-Canic M, Bolshakov VN, Coats SE, Lane EB. (2009). Severe keratin 5 and 14 mutations induce down-regulation of junction proteins in keratinocytes. Exp Cell Res. 315: 2995-3003. PMID: 19616543 Link

Chen H, Toh TK, Szeverenyi I, Ong RT, Theng CT, McLean WH, Seielstad M, Lane EB (2008). Association of Skin Barrier Genes within the PSORS4 Locus Is Enriched in Singaporean Chinese with Early-Onset Psoriasis. J Invest Dermatol. 129: 606-14. PMID: 18787534 Link

Fudge D, Russell D, Beriault D, Moore W, Lane EB and Vogl AW (2008). The intermediate filament network in cultured human keratinocytes is remarkably extensible and resilient. PLoS One 3: e2327. PMID 18523546 Link

Szeverenyi I, Cassidy AJ, Chung CW, Lee BT, Common JE, Ogg SC, Chen H, Sim SY, Goh WL, Ng KW, Simpson JA, Chee LL, Eng GH, Li B, Lunny DP, Chuon D, Venkatesh A, Khoo KH, McLean WH, Lim YP, Lane EB (2007). The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat 29: 351-360. PMID: 18033728 Link

D'Alessandro M, Coats SE, Morley SM, Mackintosh L, Tessari G, Turco A, Gerdes A-M, Pichert G, Whittaker S, Brandrup F, Broesby-Olsen S, Gomez-Lira M, Girolomoni G, Maize JC, Feldman RJ, Kato N, Koga Y, Ferguson-Smith MA, Goudie DR, Lane EB (2007). Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder? J Invest Dermatol 127: 2336-2344. PMID: 17554363 Link

Rugg EL, Horn HM, Smith FJ, Wilson NJ, Hill AJM, Magee GJ, Shemanko CS, Baty DU, Tidman JM and Lane EB (2007). Epidermolysis simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol 127: 574-80. PMID: 17039244 Link

Schweizer J, Bowden PE, Coulombe PA, Langbein L, Lane EB, Magin TM, Maltais L,Omary MB, Parry DA, Rogers MA and Wright MW (2006). New consensus nomenclature for mammalian keratins. J Cell Biol 174: 169-174. PMID: 16831889 Link

Russell D, Andrews PD, James J and Lane EB (2004). Mechanical stress induces profound remodelling of keratin filaments and cell junctions in epidermolysis bullosa simplex keratinocytes. J Cell Sci 117: 5233 PMID: 15454576 Link

Owens DW, Wilson NJ, Hill AJM, Rugg EL, Porter RM, Hutcheson AM, Quinlan RA, van Heel D, Parkes M, Jewell DP, Campbell SS, Ghosh S, Satsangi J and Lane EB (2004). Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients. J Cell Sci 117: 1989-1999. PMID: 15090596 Link

D'Alessandro M, Morley SM, Ogden P, Liovic M, Porter R and Lane EB (2004). Functional improvement of mutant keratin cells on addition of desmin: an alternative approach to gene therapy for dominant diseases. Gene Therapy 11: 1290-1295. PMID: 15215887 Link

Liovic M, Mogensen MM, Prescott AR and Lane EB (2003). Observation of keratin particles showing fast bidirectional movement colocalised with microtubules. J Cell Sci 116: 1417-1427. PMID: 12640027 Link

Owens DW and Lane EB (2003). The quest for the function of simple epithelial keratins. Bioessays 25: 748-758. PMID: 12879445 Link