Developmental Biology of the Skin
PhD and Postdoctoral Researchers
Our group is rapidly expanding and we would welcome applications from both students and more experienced postdoctoral researchers who are interested in study the skin and how it develops. Informal inquiries to Dr Smyth are welcome at any stage.
Dr Ian Smyth
Opportunities in the Smyth lab
The lab interest is the study of the development of the skin, our largest organ. As well as protecting us from our harsh external environment, the skin plays a role in immune surveillance, thermal regulation and sensory perception.Because of its exposure to the elements it is also prone to tumour development and disease.
We study the developmental steps during which the skins outermost epidermal component becomes properly anchored to the underlying dermis. We have identified a number of genes of the Fras and Frem family which are crucial for this process and which are mutated in a severe genetic disease called Fraser Syndrome (FS). FS patients develop epidermal blisters during embryonic development which cause deformities of the eyelids, limbs and hair. Using animal models for this condition we are exploring the role of the proteins encoded by these genes. They contribute to the basement membrane (BM) which can act as a reservoir for growth factors and which can control cell adhesion, tumour metastasis, and stem cell identity. We wish to determine how these proteins control the normal development of the skin and kidney by investigating their interactions with each other and with other proteins of the extracellular environment.
More generally we are interested in working on animal models of skin disease with a focus on genes crucial for the normal development of the epidermis. As a consequence the lab has strong links with various mutagenesis and targeted mapping projects both within Australia and in the UK.
Ongoing Projects include
Biochemical characterisation of the Fras and Frem proteins
Using in vitro culture of primary and established cell lines we are interested in examining how the Fras and Frem proteins affect adhesion of skin keratinocytes. In particular we are interested in exploring the interactions of these proteins with other components of the extracellular environment and how these interactions control tissue growth and differentiation.
The role of the Frem proteins in renal development
While kidney disease is a hallmark of Fraser Syndrome we know little about how the Fras and Frem proteins mediate kidney development. We are interested in optimising a technique known as Optical Projection Tomography (OPT) to visualise milestones of development and differentiation during kidney development and using this approach to study our disease models. We are also undertaking in vitro studies to investigate these defects
The role of palmitoylation in skin biology
Palmitoylation is a post-translational fatty acid modification which can profoundly affect how a protein acts within the cell. It can alter the trafficking, localisation and biological activity. We have recently shown that palmitoylation activity is required both for the differentiation and proliferation of keratinocytes and highlight important role for the process in follicle and sebaceous gland formation. We continue to investigate proteins whose function is altered by palmitoylation in the skin.
Evans T, Boochai W, Shanley S, Smyth I, Gillies S, Georgas K, Wainwright B, Chenevix-Trench G and Wicking C (2000) The spectrum of patched mutations in a collection of Australian basal cell carcinomas. Human Mutation 16(1):43-48.
Smyth I*, Ellis T*, Riley E, Bowles J, Adolphe C, Rothnagel JA, Wicking C and Wainwright, BJ (2003) Overexpression of Sonic Hedgehog suppresses embryonic hair follicle morphogenesis. Developmental Biology 263(2): 203-215 *joint authorship
Ellis T, Smyth I, Riley E, Graham S, Elliot K, Narang M, Kay GF, Wicking C and Wainwright BJ (2003) Patched1 conditional null allele in mice.Genesis 36(3):158-161
Smyth I, Ellis T, Riley E, Narang M, Mahony D, Wicking C, Rothnagel JA and Wainwright BJ (2003) Mk6a-Cre transgenic mice direct LoxP mediated recombination to the companion cell layer of the hair follicle and to the interfollicular epidermis after induction. Journal of Investigative Dermatology 122(1): 232-234.
Smyth I, Du X, Taylor M, Justice MJ, Beutler B and Jackson IJ (2004) The extra-cellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis. Proceedings of the National Academy of Sciences USA Sep 14;101(37):13560-5.
Smyth I, van Agtmael T and Jackson IJ (2004) 17th International Mouse Genome Conference. Mammalian Genome Jul;15(7): 509-14.
Jadeja S, Smyth I, Pitera JE, Taylor MS, van Haelst M, Bentley E, McGregor L, Hopkins J, Chalepakis G, Philip N, Perez Aytes A, Watt FM, Darling SM, Jackson IJ, Woolf AS, and Scambler PJ (2005) Identification of a novel gene mutated in Fraser syndrome and the mouse myelencephalic blebs (my) strain. Nature Genetics May;37(5):520-5.
Smyth I and Scambler P (2005) The genetics of Fraser Syndrome and the blebs mouse mutants. Human Molecular Genetics 14: R269-274.
Smyth I, Wilming L, Lee AW, Taylor MS, Gautier P, Barlow K, Wallis J, Martin S, Glithero R, Phillimore B, Pelan S, Andrew R, Holt K, Taylor R, McLaren S, Burton J, Bailey J, Sims S, Squares J, Plumb B, Joy A, Gibson R, Gilbert J, Hart E, Laird G, Loveland J, Mudge J, Steward C, Swarbreck D, Harrow J, North P, Leaves N, Greystrong J, Coppola M, Manjunath S, Campbell M, Smith M, Strachan G, Tofts C, Boal E, Cobley V, Hunter G, Kimberley C, Thomas D, Cave-Berry L, Weston P, Botcherby MR, White S, Edgar R, Cross SH, Irvani M, Hummerich H, Simpson EH, Johnson D, Hunsicker PR, Little PF, Hubbard T, Campbell RD, Rogers J and Jackson IJ (2006) Genomic anatomy of the Tyrp1 (brown) deletion complex. Proceedings of the National Academy of Sciences USA Feb 27 Mar 7;103(10):3704-9
Takeda H, Lyle S, Lazar AJF, Zouboulis CC, Smyth I and Watt FM (2006) Human sebaceous tumours harbour inactivating mutations in LEF1. Nature Medicine 12: 395-397
Short K, Wiradjaja F and Smyth I (2007) Let’s stick together: the role of the Fras and Frem proteins in epidermal development. IUBMB Life Jul;59(7):427-35.