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), thereby initiating basic NP patterning. Strikingly, ectopic FGF8 in the NP can induce duplicate areas, and even complex maps.
Aim 1 tests the hypothesis that FGF8 initiates a series of gene regulatory events that specifies the area map. A systematic search for genes downstream of FGF8 that have a role in cortical regionalization will use next generation deep sequencing (RNA-Seq) to compare transcriptomes of NP tissue exposed to different concentrations of FGF8 in vitro, mimicking the natural gradient of FGF8, or freshly dissected parts of the NP, representing different presumptive types of neocortex. Secondary screening will look for candidates with regional NP expression.
Aim 2 will investigate how FGF8 interacts with FGF receptors (FGFRs), and a potential endogenous inhibitor, to control development of the normal area pattern. Wild type or mutant FGFRs will be introduced into different regions of the embryonic NP with in utero electroporation. After appropriate survival times, brains will be examined for effects on FGF8 diffusion and signaling, and mature area map organization. Some prefrontal areas derive from progenitors inside the source of FGF8, and, most likely, inside a larger source of FGF17, an FGF8 family member. Fate-mapping experiments will investigate if the nested sources of FGF8 and FGF17 give rise to nested areas of prefrontal cortex.
Aim 3 builds on a new finding, namely that a major class of cortical projection neurons, mitral cells of the olfactory bulb (OB), is also generated by progenitors inside the FGF8/17 source. Experiments are proposed to determine if FGF8/17 signaling induces the OB primordium, a bounded cortical region, confirm that FGF8/17 drive mitral cell development, and identify transcription factors downstream of FGF8/17 that specify mitral cells.
This proposal focuses on the role of Fibroblast Growth Factor (FGF)8 and 17 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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