title: Akirin2 is essential for the formation of the cerebral cortex.
abstract: The proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. Premature differentiation of cells, disruption of cell cycle timing, excessive apoptosis, and/or incorrect neuronal migration signals can have devastating effects, resulting in a number of neurodevelopmental disorders involving microcephaly and/or lissencephaly. Though genes encoding many key players in cortical development have been identified, our understanding remains incomplete. We show that the gene encoding Akirin2, a small nuclear protein, is expressed in the embryonic telencephalon. Converging evidence indicates that Akirin2 acts as a bridge between transcription factors (including Twist and NF-κB proteins) and the BAF (SWI/SNF) chromatin remodeling machinery to regulate patterns of gene expression. Constitutive knockout of Akirin2 is early embryonic lethal in mice, while restricted loss in B cells led to disrupted proliferation and cell survival.
  
  
  
  We generated cortex-restricted Akirin2 knockouts by crossing mice harboring a floxed Akirin2 allele with the Emx1-Cre transgenic line and assessed the resulting embryos using in situ hybridization, EdU labeling, and immunohistochemistry.
  
  
  
  The vast majority of Akirin2 mutants do not survive past birth, and exhibit extreme microcephaly, with little dorsal telencephalic tissue and no recognizable cortex. This is primarily due to massive cell death of early cortical progenitors, which begins at embryonic day (E)10, shortly after Emx1-Cre is active. Immunostaining and cell cycle analysis using EdU labeling indicate that Akirin2-null progenitors fail to proliferate normally, produce fewer neurons, and undergo extensive apoptosis. All of the neurons that are generated in Akirin2 mutants also undergo apoptosis by E12. In situ hybridization for Wnt3a and Wnt-responsive genes suggest defective formation and/or function of the cortical hem in Akirin2 null mice. Furthermore, the apical ventricular surface becomes disrupted, and Sox2-positive progenitors are found to "spill" into the lateral ventricle.
  
  
  
  Our data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.
authors.affiliation: Department of Biology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bosch
authors.affiliation: Department of Biology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Fuller
authors.affiliation: Department of Biology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sleeth
authors.affiliation: Department of Biology and Department of Psychiatry, The University of Iowa, 143 Biology Building, Iowa City, IA, 52242, USA. Joshua-weiner@uiowa.edu.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Weiner
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C559423:Akirin2 protein, mouse; D012097:Repressor Proteins
keywords: Apoptosis; Cortical development; Dorsal telencephalon; Microcephaly; Neural progenitor; Neuronal differentiation