MOLECULAR BASIS OF TISSUE INTERACTIONS THAT REGULATE CRANIOFACIAL DEVELOPMENT

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DESCRIPTION (provided by applicant): Development of the middle and upper face rely on signaling interactions among the forebrain, the neural crest mesenchyme, and the surface ectoderm. We have determined that signals derived from the forebrain control the formation of a signaling center (Frontonasal ectodermal zone; FEZ) in the surface ectoderm that regulates growth and patterning of the middle and upper face. Further, we demonstrated that disruptions to FEZ formation produced embryos that exhibited formes frustes of Holoprosencephaly (HPE). Our long term goal is to determine the underlying molecular mechanism(s) that regulate the establishment of the FEZ and to determine how signals derived from this signaling center regulate patterned growth of the middle and upper face. Cells within the FEZ express morphogens like Shh, Fibroblast growth factor 8 (Fgf8), and Bone morphogenetic proteins (Bmps). These molecules are ideal candidates for mediating function of the FEZ and are likely targets for teratogenic insults that produce malformations within this region of the head. We hypothesize that signaling by BMPs and SHH regulate induction of Shh expression in the ectoderm, and that together, Bmps, Shh, and Fgf8 regulate function of the FEZ. In our first Specific Aim we will assess whether BMP and/or SHH signaling are directly required within the ectodermal cells for induction of Shh expression in the FEZ, and we will assess the functional consequence of FEZ formation in the absence of BMP signaling. The objective of the second Specific Aim is to examine the role of the Bmps that are expressed within the FEZ using a tissue-specific, loss-of-function approach in avian embryos. Specifically, we will assess the morphological and molecular consequence of knocking-down Bmp expression. In our third Specific Aim we will assess the role of Fgf8 in establishing the FEZ, and the role of Fgf8 in mediating the function of this signaling center. We will use genetic approaches to ablate or reduce Fgf8 expression in the forebrain and ectoderm of mouse embryos and we will assess formation of the FEZ. Additionally, to distinguish between early and late roles of Fgf8 in FEZ function, we will characterize each FEZ in a novel chimeric system. Our results will contribute to the overall understanding of the epithelial-mesenchymal interactions that regulate development of the middle and upper face and will provide a basis to understand how defects in this region arise.