Abstract

Mutations in several genes have now been identified to cause a massive and specific reduction in the total number of neurons in the human brain. The specific role of these primary microcephaly (MCPH) genes in neural progenitors has yet to be fully defined. We have found that that the products of these genes, MCPH proteins, are localized to the point of abscission in dividing cells, and we hypothesize that asymmetric cell abscission in neocortical progenitors is regulated by interactions between MCPH proteins. We will pursue this hypothesis by addressing 4 specific aims: 1) Define the complex of microcephaly proteins at the midbody ring during neurogenesis; 2) Examine the role of microcephaly proteins in the timing and location of cell abscissions in neural progenitors; 3) Determine the effects of midbody ring inheritance on subsequent neural progenitor outcomes; 4) Identify mechanisms that link cell abscissions to apical junctions in neocortical neuroepithelium. ?

Public Health Relevance

Mutations in several genes have now been identified to cause a massive and specific reduction in the total number of neurons in the human brain. The specific role of these primary microcephaly (MCPH) genes in neural progenitors has yet to be fully defined. We have found that that the products of these genes, MCPH proteins, are localized to the point of abscission in dividing cells, and we hypothesize that asymmetric cell abscission in neocortical progenitors is regulated by interactions between MCPH proteins. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH056524-11
Application #
7474198
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
1997-02-01
Project End
2013-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
11
Fiscal Year
2008
Total Cost
$342,375
Indirect Cost

  Institution

Name
University of Connecticut
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269

  Publications

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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