The Exosome Secretion of the PDGFRα in Gliogenesis and Myelination

GIVOGRI, MARIA I; PITUCH, KATARZYNA; MOYANO, ANA LIS; LOPEZ-ROSAS, AURORA; MAROTTOLI, FELECIA M; LI, GUANNAN; HU, CHENQI; VAN BREEMEN, RICHARD B; MÅNSSON, JAN-ERIC

Simposio; 45th Annual ASN Meeting; 2014

Intrinsic and extrinsic factors drive the timing of oligodendrocyte development, being the tyrosine receptor PDGFralpha a key regulator of this process. In this study we analyzed oligodendrogenesis of multipotential neural progenitors (NPs) from cells deficient in Arylsulfatase A (ASA). We found that ASA-/- NPs accumulate specific sulfatide isoforms and develop a failure to produce normal numbers of oligodendrocytes. ASA-/- NPs lose their response to PDGF-AA, a key signal required for oligodendrocyte proliferation, survival and differentiation. Interestingly, ASA deficient cells have a significant increase of exosomal secretion of PDGFralpha. The levels of PDGFralpha in ASA-/- NPs and their oligodendrogenic capacity were normalized after correction of the enzymatic defect, underlining a regulatory role for sulfatides in oligodendrogenesis. These findings highlight the importance of sulfatide homeostasis during oligodendrocyte development. Since in vitro studies showed that exosomes have a fundamental role on coordinating myelination, our findings also reveal a cellular mechanism of control with relevance for in vivo myelination. In this regard, I will also present evidence showing that exosomal shedding of PDGFralpha is a naturally occurring phenomenon during early postnatal mouse brain development operating in coordination with myelination. All together, these results suggest that exosomal shedding of PDGFralpha may contribute to regulate the sensitivity of oligodendrocyte progenitors to PDGF, with relevance in health and disease.This work was supported by NMSS Grants PP1516, RG 4439-A-2 and in part by DOD Grant contract number W81XWH-11-1-0198 to M.I.G.