title: Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination.
abstract: Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum.
authors.affiliation: Department of Biological Sciences, University of Calgary, 2500 University Drive N.W. BI-286, Calgary, AB, Canada T2N 1N4.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Rosin
authors.affiliation: Department of Psychology, Hotchkiss Brain Institute, University of Calgary, 2500 University Drive N.W., Calgary, AB, Canada T2N 1N4.
authors.forename: Brendan B
authors.initials: BB
authors.lastname: McAllister
authors.affiliation: Department of Psychology, Hotchkiss Brain Institute, University of Calgary, 2500 University Drive N.W., Calgary, AB, Canada T2N 1N4.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Dyck
authors.affiliation: Department of Cell Biology and Anatomy, Alberta Children's Hospital Institute for Child and Maternal Health, The McCaig Bone and Joint Institute, University of Calgary, Calgary, AB, Canada T2N 4N1.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Percival
authors.affiliation: Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive N.W., Room HS2275 Calgary, AB, Canada T2N 4N1. Electronic address: kurrasch@ucalgary.ca.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Kurrasch
authors.affiliation: Department of Biological Sciences, University of Calgary, 2500 University Drive N.W. BI-286, Calgary, AB, Canada T2N 1N4. Electronic address: jacobb@ucalgary.ca.
authors.forename: John
authors.initials: J
authors.lastname: Cobb
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D038081:Organogenesis / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D055415:Bone Morphogenetic Protein 4; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C465570:Shh protein, mouse; C484663:Shox2 protein, mouse
keywords: Cerebellum development; Granule cell precursors (GCPs); Purkinje cells; Short stature homeobox 2 (Shox2) gene; Sonic hedgehog (Shh)