Longterm goals of the proposed research are to understand the mechanisms that initiate development of mammalian cerebral cortex, and control formation of the neocortical area map. Findings should be relevant to a range of human disorders that stem from developmental defects in cerebral cortex. This proposal, which has three aims, is based on evidence that the signaling molecule Fibroblast Growth Factor (FGF) 8 acts as a graded morphogen in the embryonic mouse neocortical primordium (NP), and initiates a genetic cascade that leads to formation of the area map. Strikingly, ectopic FGF8 in the NP can induce duplicate areas, and even complex maps.
Aim 1 is built on a previous, systematic search for candidate genes downstream of FGF8 and next in the cascade that leads to cortical regionalization. We used deep sequencing (RNA-Seq) to compare transcriptomes of NP tissue, exposed to different concentrations of FGF8 on different time schedules, mimicking the natural gradient of FGF8, and the natural timed exposure of NP to FGF8. We have identified several candidate genes downstream of FGF8 with regional expression in the NP and a link with embryonic patterning elsewhere. We will use mouse genetics and in utero microelectroporation for gene transfer into living mouse embryos to determine the role of the candiate genes in patterning the area map.
Aim 2 will investigate how FGF8 interacts with FGF receptors (FGFRs), and how potential endogenous FGFR inhibitors and enhancers control the FGF8 grandient, and, consequently, development of the area map.
Aim 3 will investigate the olfactory bulb primordium (OBP) as a promising model system for determining how bounded areas are established in embryonic cortex. The OBP is a distinct bounded domain long before any neocortical areas. We have evidence that FGF8 can induce a secondary OBP and will investigate FGF8 induction of the OBP further in this aim. The OBP is derived from tissue immediately adjacent to the areas of prefrontal cortex. Experiments will explore how these different cortical structures are separated from one another in development. Partial motivation for our experiments here are claims of a common link between olfactory deficits and schizophrenia and autism.
This proposal focuses on the role of Fibroblast Growth Factor (FGF)8 signaling in the developing cerebral cortex. A surprisingly large number of human disorders have been genetically linked to defects in FGF signaling. Therefore, this work is likely to shed light on developmental disorders including schizophrenia, some forms of autism, and a range of human syndromes associated with cognitive impairment.
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