Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide

Qian Hea, Guanghu Wang, Sushama Wakade, Somsankar Dasgupta, Michael Dinkins, Ji Na Konga, Stefka D. Spassieva, Erhard Bieberich

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

We show here that human embryonic stem (ES) and induced pluripotent stem cell-derived neuroprogenitors (NPs) develop primary cilia. Ciliogenesis depends on the sphingolipid ceramide and its interaction with atypical PKC (aPKC), both of which distribute to the primary cilium and the apicolateral cell membrane in NP rosettes. Neural differentiation of human ES cells to NPs is concurrent with a threefold elevation of ceramide-in particular, saturated, long-chain C 16:0 ceramide (N-palmitoyl sphingosine) and nonsaturated, very long chain C24:1 ceramide (N-nervonoyl sphingosine). Decreasing ceramide levels by inhibiting ceramide synthase or neutral sphingomyelinase 2 leads to translocation of membrane-bound aPKC to the cytosol, concurrent with its activation and the phosphorylation of its substrate Aurora kinase A (AurA). Inhibition of aPKC, AurA, or a downstream target of AurA, HDAC6, restores ciliogenesis in ceramide-depleted cells. Of importance, addition of exogenous C24:1 ceramide reestablishes membrane association of aPKC, restores primary cilia, and accelerates neural process formation. Taken together, these results suggest that ceramide prevents activation of HDAC6 by cytosolic aPKC and AurA, which promotes acetylation of tubulin in primary cilia and, potentially, neural processes. This is the first report on the critical role of ceramide generated by nSMase2 in stem cell ciliogenesis and differentiation.

Original languageEnglish (US)
Pages (from-to)1715-1729
Number of pages15
JournalMolecular Biology of the Cell
Volume25
Issue number11
DOIs
StatePublished - Jun 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hea, Q., Wang, G., Wakade, S., Dasgupta, S., Dinkins, M., Konga, J. N., Spassieva, S. D., & Bieberich, E. (2014). Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide. Molecular Biology of the Cell, 25(11), 1715-1729. https://doi.org/10.1091/mbc.E13-12-0730