The bone morphogenetic proteins (Bmps) and Wnts represent two families of signaling proteins that are fundamental regulators of development. In the telencephalon - the forebrain subdivision that contains the cerebral cortex - multiple Bmps and Wnts are expressed in the dorsal midline region (DMR), where they are likely responsible for multiple developmental functions and malformation phenotypes. However, their presumed roles have remained elusive, due in part to significant functional redundancy among family members. This and other factors have greatly minimized the impact of traditional mouse genetics on elucidating Bmp and Wnt functions in telencephalic development. To overcome this limitation, we have adopted an alternative, but well established, genetic approach - lineage-specific cellular ablation. In our recently improved system, we utilize the restricted expression of a Bmp family member (Gdf7) to ablate a small subset of DMR cells in living mouse embryos. This causes marked reductions of multiple Bmp and Wnt signals, which are associated with three major defects in the telencephalon: 1) Loss of choroid plexus, the producer of cerebrospinal fluid, 2) selective cortical patterning defects, and 3) holoprosencephaly (HPE), the most common congenital malformation of the human brain. The central hypothesis driving this proposal is that DMR-dependent functions in telencephalic patterning and HPE pathogenesis are mediated by Bmp and Wnt signals. The immediate goal is to determine whether Bmp and Wnt signals are necessary and sufficient to mediate the embryonic patterning functions of the DMR. We will address this hypothesis by combining mouse genetics with explant cultures, which will be analyzed with markers and quantitative gene expression studies. K02 career development activities focus on developing a comprehensive explant approach and new DMR ablation models that allow for postnatal survival. Other personnel will consult and provide relevance to human HPE. These activities should facilitate the candidate's long-term goal of developing a research program that answers fundamental questions in early telencephalic development and disease. The insights into human HPE provide immediate relevance to public health. In addition, this project should lay the groundwork for understanding other human brain disorders that involve Bmp and Wnt signals. ? ?
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