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Roles of the Brn3 POU Domain Transcription Factors during Dorsal Root Ganglion and Spinal Cord Development

by
Min Zou
B.S., University of Science and Technology of China - 2005

Thesis Advisor: Mengqing Xiang, Ph.D.
Graduate Program Molecular Genetics, Microbiology & Immunology

CABM Building, Room 010
Piscataway

Wednesday, November 2, 2011
2:00 p.m.


Abstract

The Brn3 factors include Brn3a (POU4F1), Brn3b (POU4F2), and Brn3c (POU4F3). They belong to the POU domain transcription factor family, and are differentially expressed in central and peripheral nervous systems in the vertebrates. Previous studies have shown that all three Brn3 factors are involved in regulating the development of multiple neural lineages. Among them, Brn3a and Brn3b are expressed in the developing mouse embryonic spinal cord and dorsal root ganglion, whereas Brn3c is expressed in the dorsal root ganglion but not in the spinal cord. To fully understand the roles of Brn3 factors during the dorsal root ganglion and spinal cord development, and the mechanism to establish the proper circuits between the sensory neurons and their central targets, I utilized both loss-of-function and gain-of-function approaches to address how these developmental events are regulated by Brn3 factors. First, by analyzing the Brn3a, Brn3b single and double knockout mice, I have identified several major central afferent projection defects in Brn3a mutant animals. Throughout embryonic stages in the mutant, the nociceptive axonal projections from dorsal root ganglion sensory neurons fail to innervate the designated layers of dorsal spinal cord, and the proprioceptive projections which normally reach the ventral horn are also greatly reduced. Second, I have demonstrated that these axonal projection defects are closely associated with a comprehensive disruption of sensory neuron development in the dorsal root ganglion. In Brn3a mutant mice, subtypes of sensory neurons expressing different Trk receptors are not properly differentiated during early embryonic stages and subsequently fates of neurons belonging to different sensory modalities are altered. Meanwhile, early neurogenesis of the spinal cord is unaffected by the inactivation of either or both of Brn3a and Brn3b. Thus, Brn3a is predominantly required for the proper development of dorsal root ganglion sensory neurons and their axonal projections to the spinal cord. Finally, mis-expressed Brn3a in developing chick neural tube progenitors promotes cell cycle exit and suppresses neuron differentiation by depleting the progenitor pool. When mis-expressed in postmitotic cells in the dorsal root ganglion, Brn3a specifically suppresses the generation of TrkA-expressing cells, suggesting a consistent role for Brn3a in regulating sensory neuron specification. Together, my data demonstrate a critical role for Brn3a in generating dorsal root ganglion neuron diversity and regulating sensory afferent projections to the central targets.


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