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1 Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles Research Institute and Keck School of Medicine of the University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA
2 Division of Hematology and Oncology, Childrens Hospital Los Angeles Research Institute and Keck School of Medicine of the University of Southern California, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA
*Author for correspondence (e-mail: jgroffen{at}chla.usc.edu)
Accepted July 26, 2001
Experiments in cultured cells have implicated the molecular switch Rac in a wide variety of cellular functions. Here we demonstrate that the simultaneous disruption of two negative regulators of Rac, Abr and Bcr, in mice leads to specific abnormalities in postnatal cerebellar development. Mutants exhibit granule cell ectopia concomitant with foliation defects. We provide evidence that this phenotype is causally related to functional and structural abnormalities of glial cells. Bergmann glial processes are abnormal and GFAP-positive astroglia were aberrantly present on the pial surface. Older Abr;Bcr-deficient mice show spontaneous mid-brain glial hypertrophy, which can further be markedly enhanced by kainic acid. Double null mutant astroglia are hyper-responsive to stimulation with epidermal growth factor and lipopolysaccharide and exhibit constitutively increased phosphorylation of p38 mitogen-activated protein kinase, which is regulated by Rac. These combined data demonstrate a prominent role for Abr and Bcr in the regulation of glial cell morphology and reactivity, and consequently in granule cell migration during postnatal cerebellar development in mammals.
Key words: Rac, Bergmann glial cell, External granule cell, Cerebellar development, Null mutant, Mouse
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