title: Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly.
abstract: The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of the 1q21.1 locus has been implicated in the etiology of neurodevelopmental phenotypes; however, the role of 1q21.1 genes in neurogenesis has remained elusive. Here, we show that haploinsufficiency for Rbm8a, an exon junction complex (EJC) component within 1q21.1, causes severe microcephaly and defective neurogenesis in the mouse. At the onset of neurogenesis, Rbm8a regulates radial glia proliferation and prevents premature neuronal differentiation. Reduced Rbm8a levels result in subsequent apoptosis of neurons, and to a lesser extent, radial glia. Hence, compared to control, Rbm8a-haploinsufficient brains have fewer progenitors and neurons, resulting in defective cortical lamination. To determine whether reciprocal dosage change of Rbm8a alters embryonic neurogenesis, we overexpressed human RBM8A in two animal models. Using in utero electroporation of mouse neocortices as well as zebrafish models, we find RBM8A overexpression does not significantly perturb progenitor number or head size. Our findings demonstrate that Rbm8a is an essential neurogenesis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8A may contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Hanqian
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Louis-Jan
authors.identifier: http://orcid.org/0000-0002-9035-1327
authors.initials: LJ
authors.lastname: Pilaz
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: John J
authors.initials: JJ
authors.lastname: McMahon
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27701, Department of Psychiatry and Behavioral Sciences.
authors.forename: Christelle
authors.identifier: http://orcid.org/0000-0002-4420-3921
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Danwei
authors.identifier: http://orcid.org/0000-0003-3411-0382
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27701, Department of Cell Biology.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, Department of Cell Biology, Department of Neurobiology, and Duke Institute for Brain Sciences, Duke University Medical Center, Durham, North Carolina 27710 debra.silver@duke.edu.
authors.forename: Debra L
authors.identifier: http://orcid.org/0000-0001-9189-844X
authors.initials: DL
authors.lastname: Silver
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology*; D057895:Haploinsufficiency / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism; D038081:Organogenesis / Q000502:physiology; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C406243:RBM8A protein, human; D016601:RNA-Binding Proteins
keywords: cortical development; embryonic; microcephaly; neurogenesis; radial glia; rbm8a