title: Prion protein promotes growth cone development through reggie/flotillin-dependent N-cadherin trafficking.
abstract: The role of prion protein (PrP) is insufficiently understood partially because PrP-deficient (-/-) neurons from C57BL/6J mice seem to differentiate normally and are functionally mildly impaired. Here, we reassessed this notion and, unexpectedly, discovered that PrP(-/-) hippocampal growth cones were abnormally small and poor in filopodia and cargo-containing vesicles. Based on our findings that PrP-PrP trans-interaction recruits E-cadherin to cell contact sites and reggie microdomains, and that reggies are essential for growth by regulating membrane trafficking, we reasoned that PrP and reggie might promote cargo (N-cadherin) delivery via PrP-reggie-connected signaling upon PrP activation (by PrP-Fc-induced trans-interaction). In wild-type but not PrP(-/-) neurons, PrP activation led to (1) enhanced PrP-reggie cocluster formation, (2) reggie-associated fyn and MAP kinase activation, (3) Exo70 and N-cadherin (cargo) recruitment to reggie, (4) the preference of the growth cone for PrP-Fc as substrate, and (5) longer neurites. Conversely, PrP-reggie-induced N-cadherin recruitment was blocked by mutant TC10, the GTPase downstream of reggie, triggering exocyst-assisted cargo delivery. This implies that PrP functions in reggie-mediated signaling and cargo trafficking, thus promoting growth cone complexity and vitality and thereby growth cone elongation.
authors.affiliation: Department of Biology, University of Konstanz, 78467 Konstanz, Germany. vsevolod.bodrikov@uni-konstanz.de
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Bodrikov
authors.forename: Gonzalo P
authors.initials: GP
authors.lastname: Solis
authors.forename: Claudia A O
authors.initials: CA
authors.lastname: Stuermer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics; D020439:Growth Cones / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D010455:Peptides / Q000494:pharmacology; D011328:Prions / Q000235:genetics / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection / Q000379:methods; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; C522783:Exo70 protein, mouse; D008565:Membrane Proteins; D010455:Peptides; D011328:Prions; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; C106354:flotillins