The bone morphogenetic proteins (Bmps) and Wnts represent two families of signaling proteins that arefundamental regulators of development. In the telencephalon - the forebrain subdivision that contains thecerebral cortex - multiple Bmps and Wnts are expressed in the dorsal midline region (DMR), where they arelikely responsible for multiple developmental functions and malformation phenotypes. However, theirpresumed roles have remained elusive, due in part to significant functional redundancy among familymembers. This and other factors have greatly minimized the impact of traditional mouse genetics onelucidating Bmp and Wnt functions in telencephalic development. To overcome this limitation, we have adopted an alternative, butwell 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 causesmarked reductions of multiple Bmp and Wnt signals, which are associated with three major defects in thetelencephalon: 1) loss of choroid plexus, the producer of cerebrospinal fluid, 2) selective cortical patterningdefects, 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 patterningand HPE pathogenesis are mediated by Bmp and Wnt signals. The immediate goal is to determine whetherBmp and Wnt signals are necessary and sufficient to mediate the embryonic patterning functions of theDMR. We will address this hypothesis by combining mouse genetics with explant cultures, which will beanalyzed with markers and quantitative gene expression studies. K02 career development activities focus ondeveloping a comprehensive explant approach and new DMR ablation models that allow for postnatalsurvival. Other personnel will consult and provide relevance to human HPE. These activities should facilitatethe candidate's long term goal of developing a research program that answers fundamental questions inearly telencephalic development and disease. The insights into human HPE provide immediate relevance topublic health. In addition, this project should lay the groundwork for understanding other human braindisorders that involve Bmp and Wnt signals.
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| Cheng, Xun; Hsu, Ching-mei; Currle, D Spencer et al. (2006) Central roles of the roof plate in telencephalic development and holoprosencephaly. J Neurosci 26:7640-9 |
