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Cerebral Cortex Advance Access published online on August 5, 2004
Cerebral Cortex, doi:10.1093/cercor/bhh145
© 2004 by Oxford University Press
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Article

Functional Manipulations of Acetylcholinesterase Splice Variants Highlight Alternative Splicing Contributions to Murine Neocortical Development

Amir Dori 1, Jonathan Cohen 2, William F. Silverman 3, Yaakov Pollack 4, Hermona Soreq 5*

1 Department of Neurosurgery, Soroka University Medical Center, Beer-Sheva, Israel; Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem, Israel
2 Department of Neurosurgery, Soroka University Medical Center, Beer-Sheva, Israel
3 Department of Morphology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
4 Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
5 Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem, Israel

* To whom correspondence should be addressed. E-mail: soreq{at}cc.huji.ac.il.


  Abstract

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.

Keywords: alternative splicing; neurogenesis; neuronal migration; radial glia; readthrough acetylcholinesterase.
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