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Genetic regulation of prefrontal cortex development

  • Author(s): Cholfin, Jeremy Adam
  • Advisor(s): Rubenstein, John L. R.
  • et al.
Abstract

The prefrontal cortex (PFC) has been called "the organ of civilization" (Luria). The most anterior part of cerebral cortex, the PFC consists of multiple areas that mediate a wide range of higher-order behaviors in mammals. Despite years of intensive neuroanatomical and functional studies, little is known about the genetic mechanisms that pattern this structure during development. It has been recognized that fibroblast growth factor (FGF) signaling from the rostral patterning center could have a central role in regulating rostral telencephalic development. A subset of FGF genes are expressed in the rostral patterning center in the embryonic telencephalon. Recent evidence shows that FGFs regulate the graded expression of regulatory genes (i.e. Emx2) in the cortical neuroepithelium, which may specify the initial distribution of PFC regional subdivisions and ultimately mature areas. I have devised a novel panel of gene expression markers to study the roles of Fgf17 and Fgf8, and genetic interactions between Fgf17 and Emx2 in patterning the frontal cortex. In addition, I have identified signaling mechanisms and genetic interactions during early forebrain development that may contribute to the postnatal regionalization phenotypes. Finally, I have initiated behavioral studies through collaborations with other laboratories to investigate higher-order behaviors that are dependent on intact PFC function. I have found that Fgf17, Fgf8 and Emx2 each play unique roles in the early regionalization of the PFC, and that Fgf17 and Emx2 specifically interact on the genetic level to regulate this process. In addition, Fgf17 mutant mice exhibit circumscribed deficits in social behavior and associated selective hypo-activation of the dorsal PFC. These studies reveal that the organization of subdivisions within a higher-order cortical area is partially under genetic control, and suggest that mispatterning of the PFC via genetic mutation may contribute to abnormal behavior.

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