title: Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation.
abstract: Ranbp1, a Ran GTPase-binding protein implicated in nuclear/cytoplasmic trafficking, is included within the DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS) critical region associated with behavioral impairments including autism and schizophrenia. Ranbp1 is highly expressed in the developing forebrain ventricular/subventricular zone but has no known obligate function during brain development. We assessed the role of Ranbp1 in a targeted mouse mutant. Ranbp1(-/-) mice are not recovered live at birth, and over 60% of Ranbp1(-/-) embryos are exencephalic. Non-exencephalic Ranbp1(-/-) embryos are microcephalic, and proliferation of cortical progenitors is altered. At E10.5, radial progenitors divide more slowly in the Ranpb1(-/-) dorsal pallium. At E14.5, basal, but not apical/radial glial progenitors, are compromised in the cortex. In both E10.5 apical and E14.5 basal progenitors, M phase of the cell cycle appears selectively retarded by loss of Ranpb1 function. Ranbp1(-/-)-dependent proliferative deficits substantially diminish the frequency of layer 2/3, but not layer 5/6 cortical projection neurons. Ranbp1(-/-) cortical phenotypes parallel less severe alterations in LgDel mice that carry a deletion parallel to many (but not all) 22q11.2 DS patients. Thus, Ranbp1 emerges as a microcephaly gene within the 22q11.2 deleted region that may contribute to altered cortical precursor proliferation and neurogenesis associated with broader 22q11.2 deletion.
authors.affiliation: GW Institute for Neuroscience Department of Pharmacology and Physiology.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Paronett
authors.affiliation: GW Institute for Neuroscience Department of Pharmacology and Physiology.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Meechan
authors.affiliation: GW Institute for Neuroscience Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Karpinski
authors.affiliation: GW Institute for Neuroscience Department of Pharmacology and Physiology.
authors.forename: Anthony-Samuel
authors.initials: AS
authors.lastname: LaMantia
authors.affiliation: GW Institute for Neuroscience Department of Pharmacology and Physiology.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Maynard
mesh_terms: D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation / Q000235:genetics; D002540:Cerebral Cortex / Q000196:embryology* / Q000503:physiopathology; D004062:DiGeorge Syndrome / Q000196:embryology* / Q000235:genetics* / Q000503:physiopathology; D020547:Lateral Ventricles / Q000196:embryology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics*; D058953:Neural Stem Cells / Q000502:physiology*; D046569:Neuroepithelial Cells / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; C091775:ran-binding protein 1
keywords: basal progenitor; cell cycle; cerebral cortex; cortical development; intermediate progenitor