| Advisory Committee |
| Advisor Name |
Title |
| Cynthia Lance-Jones, PhD |
Committee Chair |
| A. Paula Monaghan, PhD |
Committee Member |
| Edda Thiels, PhD |
Committee Member |
| J. Patrick Card, PhD |
Committee Member |
| Julie Blendy, PhD |
Committee Member |
| Laura Lillien, PhD |
Committee Member |
|
Abstract
Tlx (Nr2E1) is an orphan nuclear receptor transcription factor expressed in neural progenitor cells (PCs) in the forebrain throughout development and in regions of adult neurogenesis. Tlx regulates proliferation in both embryonic and adult PCs. Loss of tlx leads to abnormalities in limbic structures resulting in alterations in emotional and cognitive behaviors. However, the precise role of tlx in the developing forebrain and how tlx contributes to the normal development of adult anatomy and behavior are not fully understood. Tlx is expressed in PCs throughout the dorsal and ventral telencephalon and the diencephalon that give rise to structures including the cerebral cortex, hippocampus, amygdala, septum, striatum, and hypothalamus. Detailed examination of tlx expression revealed that within the dorsal PC population tlx is expressed specifically in radial glial progenitors but is absent from intermediate progenitor cells (IPCs). However, in the absence of tlx IPCs are reduced throughout development, suggesting that tlx promotes the production of IPCs. To examine the role of tlx specifically in dorsal PCs we generated mice with a conditional mutation of tlx in cortical, Emx1-expressing PCs (tlxcKO). In these animals functional recombination of the floxed tlx allele occurs prior to embryonic day 12.5. TlxcKO animals show similar changes in PCs as nulls, indicating a requirement for tlx within dorsal PCs. The cerebral cortex of tlxcKO animals is reduced in surface area and thickness from birth, persisting into adulthood. As in tlx null mutants, superficial layers are specifically affected and caudal functional cortical areas, including visual cortex, are disproportionately reduced. Other dorsally-derived structures, including the hippocampus, specific nuclei of the amygdala, and the septum are reduced, whereas ventrally-derived structures are relatively unaffected. These animals exhibit a subset of the behavioral abnormalities observed in nulls, with the primary phenotype being a reduction in anxiety. Together, these findings suggest an important role for tlx in the regulation of dorsal PCs. I propose that tlx promotes divisions that produce IPCs, and that disruption of this population leads to specific alterations in adult brain structure and behavior. This model allows us to begin to make connections between early development and behavior.
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