Neurogenesis is an essential developmental process in which neural progenitors generate neurons. In the developing cerebral cortex, radial glia cells divide symmetrically to self-renew and asymmetrically to generate neurons and other progenitors. We lack a fundamental understanding of the cell biological mechanisms regulating radial glia divisions. In addition, we have a limited understanding of how radial glia divisions ar defined at the molecular level, including the role of post-transcriptional regulation. The overall objective of this proposal is to elucidate the contribution of these essential levels of regulation for neurogenesis, by exploiting a novel mouse neurogenesis mutant. This mutant is haploin-sufficient for Magoh, which is a component of the exon junction RNA binding complex (EJC). Our previous NIH-funded studies demonstrated that Magoh mutants exhibit microcephaly, with brains 30% smaller than normal, largely due to reduced neural progenitors. We found that Magoh is essential for proper mitosis of neural progenitors and discovered that Magoh regulates Lis1, a microtubule-associated protein essential for neurogenesis. Moreover we have found that Magoh controls expression of key neural progenitor determinants. Together, our discoveries point to Magoh as a novel central regulator of neurogenesis, yet we lack a fundamental understanding of how Magoh functions in the brain. We propose Magoh has two critical functions in neural progenitors: to regulate proper mitosis and to act in a post-transcriptional regulatory module controlling expression of key neurogenesis genes. Our central hypothesis is that Magoh regulates asymmetric division of radial glia by influencing the mitotic spindle and mRNA metabolism. To address this hypothesis we will pursue the following aims: First we will determine the cellular mechanism by which Magoh regulates neuron and INP production. We will use conditional genetic analysis along with live imaging of radial glia divisions in live brai slices. Second we will define how Magoh regulates mitosis by elucidating its regulation of microtubules and Lis1. We will determine how Magoh regulates Lis1 levels and if Lis1 functions downstream of Magoh in mitosis. Third, we will define the key mRNA targets of Magoh in neurogenesis and determine the role of the EJC in their regulation. Upon successful completion of these aims, we will have significantly advanced our understanding of how Magoh influences neurogenesis, by regulating both mitosis and mRNAs. Together, our proposed studies will broaden our fundamental understanding of the regulation of asymmetric division and the etiology of neurodevelopmental disorders.

Public Health Relevance

This project will advance our understanding of the genetic regulation of neural progenitor division, neurogenesis, and brain development. These processes are relevant to the etiology of brain malformations, such as microcephaly, and psychiatric disorders, such as autism. Therefore this study may eventually help in the development of diagnostic and therapeutic options for broad neurodevelopmental disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Lennox, Ashley L; Mao, Hanqian; Silver, Debra L (2018) RNA on the brain: emerging layers of post-transcriptional regulation in cerebral cortex development. Wiley Interdiscip Rev Dev Biol 7:
Mitchell, Caitlyn; Silver, Debra L (2018) Enhancing our brains: Genomic mechanisms underlying cortical evolution. Semin Cell Dev Biol 76:23-32
Pilaz, Louis-Jan; Silver, Debra L (2017) Moving messages in the developing brain-emerging roles for mRNA transport and local translation in neural stem cells. FEBS Lett 591:1526-1539
Mao, Hanqian; Brown, Hannah E; Silver, Debra L (2017) Mouse models of Casc3 reveal developmental functions distinct from other components of the exon junction complex. RNA 23:23-31
Miller, Emily E; Kobayashi, Gerson S; Musso, Camila M et al. (2017) EIF4A3 deficient human iPSCs and mouse models demonstrate neural crest defects that underlie Richieri-Costa-Pereira syndrome. Hum Mol Genet 26:2177-2191
Pilaz, Louis-Jan; Lennox, Ashley L; Rouanet, Jeremy P et al. (2016) Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain. Curr Biol 26:3383-3392
Pilaz, Louis-Jan; McMahon, John J; Miller, Emily E et al. (2016) Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain. Neuron 89:83-99
Silver, Debra L (2016) Genomic divergence and brain evolution: How regulatory DNA influences development of the cerebral cortex. Bioessays 38:162-71
Mao, Hanqian; McMahon, John J; Tsai, Yi-Hsuan et al. (2016) Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly. PLoS Genet 12:e1006282
McMahon, J J; Miller, E E; Silver, D L (2016) The exon junction complex in neural development and neurodevelopmental disease. Int J Dev Neurosci 55:117-123

Showing the most recent 10 out of 17 publications