Regulation of neural progenitor cell motility by ceramide and potential implications for mouse brain development.
We provide evidence that the sphingolipid ceramide, in addition to its pro-apoptotic function, regulates neural progenitor (NP) motility in vitro and brain development in vivo. Ceramide (N-palmitoyl d-erythro sphingosine and N-oleoyl d-erythro sphingosine) and the ceramide analog N-oleoyl serinol (S18) stimulate migration of NPs in scratch (wounding) migration assays. Sphingolipid depletion by inhibition of de novo ceramide biosynthesis, or ceramide inactivation using an anti-ceramide antibody, obliterates NP motility, which is restored by ceramide or S18. These results suggest that ceramide is crucial for NP motility. Wounding of the NP monolayer activates neutral sphingomyelinase indicating that ceramide is generated from sphingomyelin. In membrane processes, ceramide is co-distributed with its binding partner atypical protein kinase C zeta/lambda (aPKC), and Cdc42, alpha/beta-tubulin, and beta-catenin, three proteins involved in aPKC-dependent regulation of cell polarity and motility. Sphingolipid depletion by myriocin prevents membrane translocation of aPKC and Cdc42, which is restored by ceramide or S18. These results suggest that ceramide-mediated membrane association of aPKC/Cdc42 is important for NP motility. In vivo, sphingolipid depletion leads to ectopic localization of mitotic or post-mitotic neural cells in the embryonic brain, while S18 restores the normal brain organization. In summary, our study provides novel evidence that ceramide is critical for NP motility and polarity in vitro and in vivo.
Wang
Guanghu
G
Program in Developmental Neurobiology, Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, Georgia, USA.
Krishnamurthy
Kannan
K
Chiang
Ying-Wei
YW
Dasgupta
Somsankar
S
Bieberich
Erhard
E
D000199:Actins / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000276:immunology / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000502:physiology*; D009829:Oleic Acids / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects*; D014404:Tubulin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000199:Actins; D000906:Antibodies; D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D009829:Oleic Acids; D011409:Propylene Glycols; D011493:Protein Kinase C; D014404:Tubulin; D051176:beta Catenin; D020764:cdc42 GTP-Binding Protein; D000099221:Protein Kinase C zeta; C495214:N-oleoylserinol; C001996:thermozymocidin