title: The small GTPases RhoA and Rac1 regulate cerebellar development by controlling cell morphogenesis, migration and foliation.
abstract: The small GTPases RhoA and Rac1 are key cytoskeletal regulators that function in a mutually antagonistic manner to control the migration and morphogenesis of a broad range of cell types. However, their role in shaping the cerebellum, a unique brain structure composed of an elaborate set of folia separated by fissures of different lengths, remains largely unexplored. Here we show that dysregulation of both RhoA and Rac1 signaling results in abnormal cerebellar ontogenesis. Ablation of RhoA from neuroprogenitor cells drastically alters the timing and placement of fissure formation, the migration and positioning of granule and Purkinje cells, the alignment of Bergmann glia, and the integrity of the basement membrane, primarily in the anterior lobules. Furthermore, in the absence of RhoA, granule cell precursors located at the base of fissures fail to undergo cell shape changes required for fissure initiation. Many of these abnormalities can be recapitulated by deleting RhoA specifically from granule cell precursors but not postnatal glia, indicating that RhoA functions in granule cell precursors to control cerebellar morphogenesis. Notably, mice with elevated Rac1 activity due to loss of the Rac1 inhibitors Bcr and Abr show similar anterior cerebellar deficits, including ectopic neurons and defects in fissure formation, Bergmann glia organization and basement membrane integrity. Together, our results suggest that RhoA and Rac1 play indispensable roles in patterning cerebellar morphology.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalaka
authors.initials: S
authors.lastname: Mulherkar
authors.affiliation: University of Houston, Houston, TX 77004, USA.
authors.forename: Mohammad Danish
authors.initials: MD
authors.lastname: Uddin
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Couvillon
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children׳s Hospital, Houston, TX 77030, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Roy V
authors.initials: RV
authors.lastname: Sillitoe
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, M.S. BCM 295, Houston, TX 77030, USA. Electronic address: tolias@bcm.edu.
authors.forename: Kimberley F
authors.initials: KF
authors.lastname: Tolias
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D019521:Body Patterning / Q000235:genetics; D002465:Cell Movement; D002531:Cerebellum / Q000196:embryology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics*; D009457:Neuroglia / Q000502:physiology; D009479:Neuropeptides / Q000096:biosynthesis*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis*; D020741:rho GTP-Binding Proteins / Q000235:genetics*; D020742:rhoA GTP-Binding Protein
chemical_list: C484145:Abr protein, mouse; D004965:Estrogen Antagonists; D020690:GTPase-Activating Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D013629:Tamoxifen; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr; C526380:RhoA protein, mouse; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Bergmann glia; Cell shape changes; Foliation; Granule cell precursors; Granule cells; Rho GTPases