Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Animals, Newborn
-
Astrocytes / metabolism
-
Astrocytes / pathology*
-
Behavior, Animal
-
Cerebellum / cytology
-
Cerebellum / growth & development*
-
Cerebellum / metabolism
-
GTPase-Activating Proteins
-
Gene Expression Regulation, Developmental
-
Glial Fibrillary Acidic Protein / metabolism
-
Gliosis / genetics
-
Mesencephalon / metabolism
-
Mesencephalon / pathology
-
Mesencephalon / physiopathology
-
Mice
-
Mice, Knockout
-
Mice, Transgenic
-
Mitogen-Activated Protein Kinases / metabolism
-
Oncogene Proteins / genetics*
-
Oncogene Proteins / metabolism
-
Phosphorylation
-
Protein-Tyrosine Kinases*
-
Proteins / genetics*
-
Proteins / metabolism
-
Proto-Oncogene Proteins c-bcr
-
Proto-Oncogene Proteins*
-
Purkinje Cells / metabolism
-
Rhombencephalon / growth & development
-
Rhombencephalon / metabolism
-
Rhombencephalon / pathology
-
p38 Mitogen-Activated Protein Kinases
-
rac GTP-Binding Proteins / metabolism*
Substances
-
Abr protein, mouse
-
GTPase-Activating Proteins
-
Glial Fibrillary Acidic Protein
-
Oncogene Proteins
-
Proteins
-
Proto-Oncogene Proteins
-
Protein-Tyrosine Kinases
-
Bcr protein, mouse
-
Proto-Oncogene Proteins c-bcr
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
rac GTP-Binding Proteins