Marie Curie Fellowship 2014 Recruiting Form
Principal Investigator:
Prof. Robert Kelsh
Department:
Biology and Biochemistry and Centre for Regenerative Medicine
Link to research webpage:
http://www.bath.ac.uk/bio-sci/contacts/academics/robert_kelsh/
Short description of research area to investigate with a potential MC Fellow
(Please keep within this page):
Genotype-phenotype correlations in SOX10 neurocristopathies
SOX10 is a major transcription factor controlling multiple aspects of neural crest and
oligodendrocyte development, including fate specification of diverse cell-types from multipotent
neural crest (stem) cells and differentiation of glial cell-types [1]. In humans, SOX10 mutations have
been identified in Waardenburg Syndrome Types 2 and 4, characterised by abnormalities of
pigmentation with and without Hirschsprung disease respectively, and in a more severe neurological
variant, PCWH (Peripheral demyelinating neuropathy–Central dysmyelinating leukodystrophy–
Waardenburg syndrome–Hirschsprung disease), as well as some rarer variants. In total, around 100
SOX10 mutations have been described in these conditions. However, disappointingly, genotypephenotype correlations remain largely mysterious for these mutations. The exception is the PCWH
mutations, the severe phenotype of which corresponds to mutations generating truncated proteins
with dominant negative activity and in which the mRNAs escape the nonsense-mediated decay
pathway [2]. But how the other specific protein variants generate the specific phenotypic
characteristics in the other conditions remains only very poorly understood. The major problem here
has been that in vitro studies of the cellular localization and phenotypic effects of these mutant
proteins has been much less informative than we hoped [3]. We consider that this is due to the
inability of these cell culture systems to fully recapitulate the complex environment of the
developing neural crest. Instead, an in vivo model is required. Partnering with a French consortium
led by Prof. Nadege Bondurand (INSERM), we wish to explore a novel zebrafish rescue assay as an
accessible and rapid in vivo model system to assess SOX10 proteins. We have previously
characterised multiple zebrafish Sox10 mutants and shown that SOX10 function is largely conserved
between fish and mammals [4-6]. Transient transgenic rescue of zebrafish sox10 mutants with wildtype SOX10 protein rescues neural crest phenotypes. In this project, we intend to use this assay to
assess systematically the in vivo activity of human mutant SOX10 proteins in the melanocyte, enteric
neuron and glial lineages. This work, together with complementary studies by our consortium
partners and our ongoing work on the gene regulatory networks involving Sox10 [7], will lead to a
deeper understanding of the genotype-phenotype correlation for this crucial transcription factor, as
well as having practical application in genetic counselling.
1. Kelsh, Bioessays, 2006. 28, 788-798. 2. Inoue et al., Nat Genet, 2004. 36, 361-9.
3. Pingault
et al., Hum Mutat, 2010. 31, 391-406. 4. Carney et al., Development, 2006. 133, 4619-30.
5. Elworthy et al., Development, 2003. 130, 2809-2818. 6. Dutton et al., Development, 2001. 128,
4113-4125.
7. Greenhill et al., PLoS Genet, 2011. 7, e1002265.