Analysis of spontaneous mutations in rodents and humans has proven invaluable in identifying molecular mechanisms essential to brain development. Most notably, proteins essential to patterned migration of cortical neurons have been identified through genetic analyses and positional cloning. In contrast, there have been few spontaneous mutations that have led to the identification of pathways involved in the control of cytokinesis and associated cellular dynamics that occur throughout neurogenesis at the surface of the ventricles. The regulation of cytokinesis plays a central role in neocortical neurogenesis, and may determine the fates of newly generated daughter cells. In the first period of this grant we discovered a novel mutant, flathead, which has now revealed an essential molecular mechanism that operates to regulate cytokinesis and neurogenesis in neuronal progenitors. The CNS-specific phenotype of the flathead mutant is characterized by severe micrencephaly with alterations in the relative numbers of different neuronal cell types, and in abnormal neuronal hypertrophy. A positional cloning strategy was used to identify the flathead mutation as a mutation in the Citron-kinase gene (CitronK or CitK) located on the long arm of rat and human chromosome 12. The flathead mutation is a single base deletion in exon 1 that results in a nonsense codon and absence of CitronK protein expression in proliferative zones. CitronK protein is concentrated at the VZ surface at adherens unctions and cytokinesis furrows. We hypothesize that CitK, which contains multiple protein interaction domains, links fate determining signals with cytoskeletal restructuring at the VZ surface. We propose to use a combination of imaging experiments, in vivo transfection, and biochemical experiments to further elucidate a cellular and molecular pathway necessary for neurogenesis.

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National Institute of Mental Health (NIMH)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Sieber, Beth-Anne
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University of Connecticut
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Chen, Fuyi; Becker, Albert; LoTurco, Joseph (2016) Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery. Curr Protoc Pharmacol 72:14.37.1-12
Chen, Fuyi; Rosiene, Joel; Che, Alicia et al. (2015) Tracking and transforming neocortical progenitors by CRISPR/Cas9 gene targeting and piggyBac transposase lineage labeling. Development 142:3601-11
Che, Alicia; Girgenti, Matthew J; LoTurco, Joseph (2014) The dyslexia-associated gene DCDC2 is required for spike-timing precision in mouse neocortex. Biol Psychiatry 76:387-96
Soh, Heun; Pant, Rima; LoTurco, Joseph J et al. (2014) Conditional deletions of epilepsy-associated KCNQ2 and KCNQ3 channels from cerebral cortex cause differential effects on neuronal excitability. J Neurosci 34:5311-21
Centanni, T M; Booker, A B; Sloan, A M et al. (2014) Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex. Cereb Cortex 24:1753-66
Glasgow, Stacey M; Zhu, Wenyi; Stolt, C Claus et al. (2014) Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes. Nat Neurosci 17:1322-9
Chen, Fuyi; Becker, Albert J; LoTurco, Joseph J (2014) Contribution of tumor heterogeneity in a new animal model of CNS tumors. Mol Cancer Res 12:742-53
Chen, Fuyi; Maher, Brady J; LoTurco, Joseph J (2014) piggyBac transposon-mediated cellular transgenesis in mammalian forebrain by in utero electroporation. Cold Spring Harb Protoc 2014:741-9
Siddiqi, Faez; Chen, Fuyi; Aron, Abraham W et al. (2014) Fate mapping by piggyBac transposase reveals that neocortical GLAST+ progenitors generate more astrocytes than Nestin+ progenitors in rat neocortex. Cereb Cortex 24:508-20
Szalkowski, Caitlin E; Fiondella, Christopher F; Truong, Dongnhu T et al. (2013) The effects of Kiaa0319 knockdown on cortical and subcortical anatomy in male rats. Int J Dev Neurosci 31:116-22

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