Heparanase 2 and LRIG2 direct functional differentiation of peripheral nerves
| Dates: | 20 January 2015 |
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| Times: | 13:00 - 14:00 |
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| What is it: | Seminar |
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| Organiser: | Faculty of Life Sciences |
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| Who is it for: | University staff |
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| Speaker: | Adrian Woolf |
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Part of the Tissue Systems seminar series. Growth factor signalling drives key steps in the motor neuron lineage. Critically, what is poorly understood is how signalling is fine tuned to avoid over- or underactivity, either of which could fatally compromise the generation of functional neuro-muscular units. Our contention is that Hpse2, an endogenous inhibitor of the enzyme activity of classical heparanase, and Lrig2, a member of a family of plasma membrane proteins that control growth factor signalling, are key components of such a regulatory network. With colleagues in the Centre for Genomic Medicine, we discovered that either HPSE2 or LRIG2 can be mutated in urofacial syndrome, a congenital motor neuropathy. Applying these human discoveries to animal models provides an excellent chance to increase our knowledge of how motor neurons normally develop and differentiate. With colleagues in the Faculty for Life Sciences, we created the first vertebrate model of urofacial syndrome in Xenopus. Hpse2 knockdown caused skeletal muscle paralysis, dysmorphic motor nerves and deregulated growth factor signalling. Moreover, Hpse2 and Lrig2 are normally detected in the ventrolateral domain of the neural tube, in growth cones of neurites, and in myotomes, supporting roles for the two proteins in neuron specification, axon growth and synaptogenesis, respectively. Diseases affecting peripheral nerves affect 2% of the general population and produce unpleasant and crippling symptoms lasting for years. Curative treatments are urgently needed but are non-existent. Our ongoing studies to clarify processes underpinning normal motor neuron development and differentiation will inform the future logical design of novel biological therapies for peripheral neuropathies (Daly SB et al. Am J Hum Genet 11:963-9, 2010; Stuart HM, Roberts NA et al. J Am Soc Nephrol epub ahead of print PMID: 25145936; Stuart HM et al. Am J Hum Genet 92:259-64, 2013; Roberts NA et al. Hum Mol Genet 23:4302-14, 2014)
Speaker
Adrian Woolf
Organisation: University of Manchester
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Lecture Theatre
Michael Smith Building
Manchester
