Molecular Mechanisms of Cerebral Cortical Patterning

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DESCRIPTION (provided by applicant): The broad goal of this research is to identify the mechanisms that generate the area map of the mammalian cerebral cortex. Using the innovative method of in utero electroporation in living mouse embryos we have found evidence that the signaling molecule FGF8 specifies positional identity in the neocortex from a source in the anterior telencephalon. Modifying the endogenous anterior FGF8 signal shifts areas along the anterior/posterior (A/P) axis of the neocortex, and introducing a new posterior source of FGF8 elicits a partial area duplication with the formation of ectopic somatosensory barrel fields. The first aim of these studies is to determine if FGF8 can act as a master signal that regulates the patterning and differentiation of the cortical area map along the A/P axis. Experiments will utilize in utero electroporation to manipulate FGF8 signaling, and the area map will be analyzed postnatally when neocortical areas are identifiable by classic connectional and cytoarchitectonic criteria. The second aim is to test the hypothesis that the anterior FGF8 source interacts with a second source of signaling proteins, the cortical hem, proposed to regulate cortical patterning along the medial/lateral axis. Such an interaction would promote coordination of patterning along the two major axes of the cerebral cortex. The third aim is to clarify the FGF signaling mechanism that patterns the cortical primordium. Using electroporation of FOF and FGF receptor constructs, we will determine which FGF family members, in addition to FGF8, may constitute the endogenous patterning signal, which receptors mediate the signal, and whether the FGF signal acts to pattern the cortical primordium directly or via a relay mechanism. Finally, we will attempt to identify molecular mechanisms that lie downstream of FGF signaling in area patterning. In particular, to analyze the relation between FGF8 and the transcription factor Emx2, also implicated in A/P cortical patterning, we will employ electroporation-mediated gene transfer into a mouse line lacking Emx2 function. Several human birth defects that involve skeletal and CNS abnormalities have been traced to mutations in the FGF receptor FGFR3, which encodes a high-affinity FGF8 receptor. In particular, these mutations lead to hitherto unexplained defects of cerebral cortical development. The focus of the proposed studies on FGF8 and FGFR3 signaling in early cortical patterning should clarify how these defects are generated. More generally, an understanding of the molecular mechanisms that pattern the cerebral cortex should shed light on genetic disorders that lead to malformation and mispatterning of this part of the brain.