Roles of the GPI-anchored proteins PrP and Thy-1 in axon growth and regeneration

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In contrast to mammals, retinal ganglion cell (RGC) axons in fish regenerate successfully after optic nerve lesion. Recent own evidence suggests that the ability of fish RGCs to upregulate growth-associated molecules, such as the microdomain-forming reggie proteins, is causally linked to successful regeneration. Our recent results show that the GPI-anchored prion proteins, fish PrP-1 and PrP-2 (PrPc in mammals), as well as Thy-1 also represent growth-associated proteins. Interestingly, PrP and Thy-1 cocluster in reggie microdomains and communicate with associated signal transduction molecules and regulate Rho-GTPases and actin dynamics. In this proposal, 1.) the contribution of PrP and Thy-1 to axon regeneration in vivo and to axogenesis and process formation in single cells in vitro will be analysed using morpholino and siRNA-mediated knockdown and protein overexpression. 2.) Furthermore, signalling molecules which communicate with PrP and Thy-1 – through their association with the reggies - and how they regulate Rho-GTPases and actin dynamics will be determined, and 3.) whether and how they promote the recruitment of specific membrane proteins, process extension and axon growth. This work aims at elucidating molecular mechanisms underlying axon regeneration and at providing new insights into the function(s) of PrP and Thy-1 which are well known but their role has remained elusive.