Genetic Analysis of Forebrain Patterning & Neurogenesis

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DESCRIPTION (provided by applicant): Our cerebral hemispheres are what we use for our highest intellectual functions. When they do not form normally during development, devastating disorders ensue. The most common developmental forebrain defect is holoprosencephaly, in which the hemispheres fail to separate. Despite the importance of cerebral hemisphere development to normal brain function, little is known about the mechanisms that transform a simple sheet of embryonic neural precursor cells into the structurally complex adult cerebral hemispheres. The goal of this study is to understand how two families of secreted signaling factors, the BMPs and FGFs, function in early development of the hemispheres. Specifically, the aims are to determine if these factors are required in vivo to induce the formation of the hemispheres, to pattern their lateral and ventral areas, to form the midline that separates them, and to regulate each others activity as well as the activity of another factor essential in midline formation, SHH. In mice, a direct genetic test of the role of FGFs and BMPs in these processes in vivo has previously been difficult because these facotrs also play essential roles in the embryo prior to the onset of neural development. To get around this problem, a conditional genetic approach is used whereby multiple BMP and FGF receptor genes are deleted specifically in the embryonic cerebral hemispheres without affecting their function in the rest of the embryo. In both humans and mice, mutations in the SHH gene cause a loss of the cerebral midline, and hence holoprosencephaly. A question that remains unanswered is how SHH, which is expressed on the ventral side of the hemispheres, is required for forming not only the ventral midline, but also the dorsal midline. Preliminary evidence indicates that FGFs and BMPs are essential in forming ventral, rostral, and dorsal midline structures and that FGFs act downstream of SHH in this process. This evidence suggests that SHH acts in a signaling cascade operating from ventral to dorsal midline through FGF and BMP signaling and provides a mechanism by which SHH in humans and mice leads to holoprosencephaly.