Functional manipulations of acetylcholinesterase splice variants highlight alternative splicing contributions to murine neocortical development.
Proliferation and differentiation of mammalian central nervous system progenitor cells involve concertedly controlled transcriptional and alternative splicing modulations. Searching for the developmental implications of this programming, we manipulated specific acetylcholinesterase (AChE) splice variants in the embryonic mouse brain. In wild type mice, 'synaptic' AChE-S appeared in migrating neurons, whereas the C-terminus cleaved off the stress-induced AChE-R variant associated with migratory radial glial fibers. Antisense suppression of AChE-R reduced neuronal migration, allowing increased proliferation of progenitor cells. In contrast, transgenic overexpression of AChE-R was ineffective, whereas transgenic excess of enzymatically active AChE-S or inactive AChE-Sin suppressed progenitors proliferation alone or both proliferation and neuronal migration, respectively. Our findings attribute to alternative splicing events an interactive major role in neocortical development.
Dori
Amir
A
Department of Neurosurgery, Soroka University Medical Center, Beer-Sheva, Israel.
Cohen
Jonathan
J
Silverman
William F
WF
Pollack
Yaakov
Y
Soreq
Hermona
H
D000110:Acetylcholinesterase / Q000235:genetics*; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D002384:Catalysis; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002552:Cerebral Ventricles / Q000254:growth & development / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000201:enzymology* / Q000254:growth & development*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000502:physiology
D000963:Antimetabolites; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D000110:Acetylcholinesterase; D001973:Bromodeoxyuridine