The regulation of cortical development by Neurogenin2 Public Deposited

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  • March 22, 2019
Creator
  • Hand, Randal Alan
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • The mammalian nervous system consists of complex neuronal networks formed by extremely diverse sub-groups of neurons located throughout the body. Neurons of the cerebral cortex form neural circuits with the brain and spinal cord allowing for mammals to sense and interact with their environment. The majority of neurons within the cerebral cortex are classified into two groups: inhibitory GABAergic interneurons and excitatory glutamatergic pyramidal neurons. Pyramidal neurons are the largest population of neurons accounting for approximately eighty percent of all neurons within the cerebral cortex. Pyramidal neurons have several defining features including the use of glutamate as an excitatory neurotransmitter, the mode in which they migrate along radial glia to reach their final location, a unipolar dendritic morphology, and a long projecting axon. Within the cerebral cortex, the basic helix loop helix transcription factor, Neurogenin2 regulates the acquisition of many of the cardinal features of pyramidal neurons. Initially, Neurogenin2 was identified based on its ability to promote neuronal differentiation (proneural function) within the peripheral and central nervous systems. Elegant genetic studies demonstrated that Neurogenin2 also specifies the expression of glutamate as the neurotransmitter for pyramidal neurons. My research identified novel roles for Neurogenin2 including the regulation of radial glia guided migration, their pyramidal dendritic morphology and the axon projection of pyramidal neurons. In addition, I found that a C-terminal tyrosine phosphorylation site in Neurogenin2 was necessary to promote migration and the acquisition of the appropriate dendritic morphology. Loss of function assays revealed that Neurogenin2 regulates the guidance of callosal axons and formation of the corpus callosum. Here, I propose that Neurogenin2 is a master regulator of glutamatergic pyramidal neurons phenotype. Neurogenin2 regulates many aspects required for proper circuit formation including the physical location of neurons, the ability of a neuron to receive afferent signals through proper dendritic morphogenesis, and the ability of a neuron to innervate the proper tissue through the guidance of its long projecting axon. Since Neurogenin2 regulates these aspects of neural circuit formation, it is of no surprise that Neurogenin2 and many of the genes regulated by Neurogenin2 are implicated in mental retardation, epilepsy, and autism spectrum disorders.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Medicine in the department of Pharmacology."
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  • Polleux, Franck
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  • Chapel Hill, NC
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  • Open access
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