Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells

• Published in: Nature neuroscience Vol. 12; no. 6; pp. 735 - 744
• Main Authors: Miller, Freda D, Gauthier-Fisher, Andrée, Lin, Dan C, Greeve, Melissa, Kaplan, David R, Rottapel, Robert
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2009
• Subjects: Animals; Cell Cycle Proteins - genetics; Cell Differentiation - genetics; Cell division; Cell Polarity - genetics; Cell Proliferation; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - embryology; Down-Regulation - genetics; Dyneins; Gene Expression Regulation, Developmental - genetics; Genetic aspects; Guanine Nucleotide Exchange Factors - genetics; Mice; Microtubule-Associated Proteins - genetics; Microtubules; Mitosis - genetics; Neocortex; Neurogenesis; Neurogenesis - physiology; Neurons; Neurons - cytology; Neurons - metabolism; Nuclear Proteins - genetics; Physiological aspects; Proto-Oncogene Proteins - genetics; Rho Guanine Nucleotide Exchange Factors; rhoA GTP-Binding Protein - genetics; Signal Transduction - genetics; Spindle Apparatus - genetics; Stem Cells - cytology; Stem Cells - metabolism; t-Complex Genome Region; Canada; Toronto Ontario Canada
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2339

The mechanisms that regulate symmetric, proliferative divisions versus asymmetric, neurogenic divisions of mammalian neural precursors are still not well understood. We found that Lfc (Arhgef2), a Rho-specific guanine nucleotide exchange factor that interacts with spindle microtubules, and its negative regulator Tctex-1 (Dynlt1) determine the genesis of neurons from precursors in the embryonic murine cortex. Specifically, genetic knockdown of Arhgef2 in cortical precursors either in culture or in vivo inhibited neurogenesis and maintained cells as cycling radial precursors. Conversely, genetic knockdown of Dynlt1 in radial precursors promoted neurogenesis and depleted cycling cortical precursors. Coincident silencing of these two genes indicated that Tctex-1 normally inhibits the genesis of neurons from radial precursors by antagonizing the proneurogenic actions of Lfc. Moreover, Lfc and Tctex-1 were required to determine the orientation of mitotic precursor cell divisions in vivo. Thus, Lfc and Tctex-1 interact to regulate cortical neurogenesis, potentially by regulating mitotic spindle orientation.