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

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...

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Autores principales: He, Qian, Wang, Guanghu, Wakade, Sushama, Dasgupta, Somsankar, Dinkins, Michael, Kong, Ji Na, Spassieva, Stefka D., Bieberich, Erhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038499/
https://www.ncbi.nlm.nih.gov/pubmed/24694597
http://dx.doi.org/10.1091/mbc.E13-12-0730
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author He, Qian
Wang, Guanghu
Wakade, Sushama
Dasgupta, Somsankar
Dinkins, Michael
Kong, Ji Na
Spassieva, Stefka D.
Bieberich, Erhard
author_facet He, Qian
Wang, Guanghu
Wakade, Sushama
Dasgupta, Somsankar
Dinkins, Michael
Kong, Ji Na
Spassieva, Stefka D.
Bieberich, Erhard
author_sort He, Qian
collection PubMed
description 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 C(24:1) 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 C(24:1) 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.
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spelling pubmed-40384992014-08-16 Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide He, Qian Wang, Guanghu Wakade, Sushama Dasgupta, Somsankar Dinkins, Michael Kong, Ji Na Spassieva, Stefka D. Bieberich, Erhard Mol Biol Cell Articles 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 C(24:1) 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 C(24:1) 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. The American Society for Cell Biology 2014-06-01 /pmc/articles/PMC4038499/ /pubmed/24694597 http://dx.doi.org/10.1091/mbc.E13-12-0730 Text en © 2014 He et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
He, Qian
Wang, Guanghu
Wakade, Sushama
Dasgupta, Somsankar
Dinkins, Michael
Kong, Ji Na
Spassieva, Stefka D.
Bieberich, Erhard
Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
title Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
title_full Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
title_fullStr Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
title_full_unstemmed Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
title_short Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
title_sort primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038499/
https://www.ncbi.nlm.nih.gov/pubmed/24694597
http://dx.doi.org/10.1091/mbc.E13-12-0730
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