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Determining the mechanisms of cerebral cortical development is essential to understanding the functions, disorders, and evolution of the brain. My research focuses on the embryonic and early postnatal development of cerebral cortex in the mouse. Specific questions include: how part of the embryonic neuroepithelium is divided, or “patterned” into the neocortex and hippocampus; how different hippocampal neuronal cell types are specified; and how a consistent map of functionally distinct areas is laid out in neocortex. To a developmental biologist the cerebral cortex may seem too complex a system for studies of tissue patterning and cell type specification. My lab, however, has contributed to a model in which the embryonic cortex is initially patterned by secreted signaling molecules, including Fibroblast Growth Factor (FGF) 8, and the Wnt protein, Wnt3a, together with downstream transcription factors, in much the same way as in the rest of the embryo. FGF8 disperses from an anterior source to establish the anterior to posterior (A/P) axis of the neocortical area map. Wnt3a influences the medial to lateral (M/L) axis and is also required for development of the hippocampus. Together, FGF8 and Wnt3a shape expression gradients of transcription factor genes that control the size and position of neocortical areas as well as hippocampal growth. This model is still incomplete. For example, how sharp area boundaries arise from graded gene expression is unclear. Classically, for this step, a mechanism specific to the nervous system is proposed, namely the growth of axons from the thalamus into the neocortex. Yet previous findings indicate that precise guidance cues lie within nascent neocortical areas. To identify area-specific axon guidance molecules, we plan to harvest in cells from a mouse in which sensory areas are marked by green fluorescence, and compare the transcriptomes of different areas using RNA-Seq. A major outstanding task is to determine if our model of cortical patterning, based on studies of the mouse, holds for larger, multi-folded (gyrencephalic) brains of carnivores and primates. Common features of the area map, conserved across mammals, suggest the model could generalize, and early evidence from a study of the gyrencephalic ferret supports this hypothesis.
Methods: Candidate genes are identified and their function altered using mouse genetics and a fine-scale method of in utero microelectroporation that we pioneered. The cortical phenotype of mice in which gene function is altered is analyzed by area-specific gene and protein expression and connectivity, and occasionally by behavior. We discovered, for instance, that part of the hippocampus is shrunken in mice deficient in BMP signaling, and that these mice were "fearless" in situations that would normally induce anxiety, supporting a new view of hippocampal function. Cell type specific transcriptomes will be identified with single cell RNA-Seq.
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