The function of Reggie (and PrP) in cargo trafficking underlying axon growth, regeneration and synapse formation

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The microdomain proteins reggie-1 and -2 are essential for axon growth and their upregulation promotes regeneration of fish and mammalian retinal ganglion cell axons in vivo. This is causally linked with the ability of reggies to coordinate - together with the cellular prion protein (PrP) - the recruitment of N-cadherin to the growth cone of hippocampal neurons, of E-cadherin to adherens junctions of epithelial cell contact sites and of the T cell receptor to the T cell cap. Our current concept explains how reggie (and PrP) support such diverse functions: they participate in the turnover and targeted delivery of membrane proteins in a cell type specific manner. This implies that reggie (and PrP) regulate cargo trafficking and recycling, which is consistent with the observation that reggie (and PrP) in Hela cells associate with a tubulo-vesicular transport system which is Rab11, Arf6, EHD-1 and sorting nexin (SNX)4-positive, depends on the intact microtubule and actin cytoskeleton and contains E-cadherin as cargo. In order to understand how reggie (and PrP) control cargo supply to growing axons and support regeneration we will analyse the interaction of reggie (and PrP) with GTPases (Rab11, Arf6, TC10) and membrane scaffolding proteins (of the SNX and EHD families) with functions in cargo sorting and trafficking. A function of reggie in trafficking suggests that reggie (together with PrP) participates in the formation and regulation of spine synapses and the recruitment of N-cadherin, glutamate AMPA and NMDA receptor subunits. Our results will elucidate a novel sorting and recycling pathway which depends on reggies (and PrP) and which is essential for neuronal differentiation, synapse formation and repair.