Cerebral Cortex Advance Access originally published online on August 5, 2004
Cerebral Cortex 2005 15(4):419-430; doi:10.1093/cercor/bhh145
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Cerebral Cortex V 15 N 4 © Oxford University Press 2004; all rights reserved
Functional Manipulations of Acetylcholinesterase Splice Variants Highlight Alternative Splicing Contributions to Murine Neocortical Development
1 Department of Neurosurgery, Soroka University Medical Center, Beer-Sheva, Israel, 2 Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem, Israel, 3 Department of Morphology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel and 4 Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Address correspondence to Hermona Soreq, Department of Biological Chemistry, Institute of Life Sciences, The Edmond J. Safra Campus, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel. Email: soreq{at}cc.huji.ac.il.
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.
Key Words: alternative splicing • neurogenesis • neuronal migration • radial glia • readthrough acetylcholinesterase
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