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.
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.
|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|
|Silver, Debra L (2016) Genomic divergence and brain evolution: How regulatory DNA influences development of the cerebral cortex. Bioessays 38:162-71|
|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|
|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|
|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|
|Singh, Sandeep K; Stogsdill, Jeff A; Pulimood, Nisha S et al. (2016) Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1Î± and NL1 via Hevin. Cell 164:183-96|
|Pilaz, Louis-Jan; Silver, Debra L (2015) Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain. Wiley Interdiscip Rev RNA 6:501-15|
|Boyd, J Lomax; Skove, Stephanie L; Rouanet, Jeremy P et al. (2015) Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex. Curr Biol 25:772-9|
|Mao, Hanqian; Pilaz, Louis-Jan; McMahon, John J et al. (2015) Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly. J Neurosci 35:7003-18|
|McMahon, John J; Shi, Lei; Silver, Debra L (2014) Generation of a Magoh conditional allele in mice. Genesis 52:752-8|
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