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Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide
- Source :
- Molecular Biology of the Cell
- Publication Year :
- 2014
-
Abstract
- Human embryonic stem and induced pluripotent stem cell–derived neuroprogenitors (NPs) develop primary cilia. Ciliogenesis depends on the sphingolipid ceramide and its interaction with atypical PKC, both of which distribute to the primary cilium and the apicolateral cell membrane in NP rosettes.<br />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 C16:0 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.
- Subjects :
- Ceramide
Cellular differentiation
Organogenesis
Induced Pluripotent Stem Cells
Spindle Apparatus
Biology
Sphingomyelin phosphodiesterase
Ceramides
Histone Deacetylase 6
Histone Deacetylases
chemistry.chemical_compound
Mice
Cytosol
Neural Stem Cells
Tubulin
Ciliogenesis
Animals
Humans
Cilia
Molecular Biology
Ceramide synthase
Embryonic Stem Cells
Protein Kinase C
Cytoskeleton
Aurora Kinase A
Cell Membrane
Acetylation
Cell Differentiation
Cell Biology
Lipid signaling
Articles
Sphingolipid
Cell biology
Enzyme Activation
Protein Transport
Sphingomyelin Phosphodiesterase
chemistry
Proteolysis
Sphingomyelin
Subjects
Details
- ISSN :
- 19394586
- Volume :
- 25
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Molecular biology of the cell
- Accession number :
- edsair.doi.dedup.....bcf69feecfd5ca7d66a2a9b9d1dbd66b