BMP-Mediated Tissue Interactions that Pattern the Face

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DESCRIPTION (provided by applicant): My long-term objective is to define the cellular and molecular basis of tissue interactions that control aspects of craniofacial development. Understanding how development of the brain and face normally occurs will afford a better understand of how malformations arise within these tissues. From these insights, we will be able to generate therapeutic approaches to treat craniofacial malformation sequences. My multidisciplinary training has focused on development of the craniofacial musculoskeletal system using biochemical, molecular, cellular, histological, and morphological approaches. The work proposed in this application stems from this training, and forms the basis for an R01 application at a later date. The skeleton of the midface is derived from neural crest cells located in the frontonasal and maxillary processes, and requires signaling interactions with neighboring tissues for proper patterning. I hypothesize that molecular interactions occurring between the brain and cells in the frontonasal process establish regional characteristics within the neural crest and facial ectoderm and that some of these interactions are mediated by Bone morphogenetic proteins (Bmps). To test this, I will use retroviral gene delivery to activate or suppress specific signaling pathways within the brain, neural crest, and facial ectoderm of chick embryos. Specifically, I will alter the dorsoventral character of the forebrain and assess molecular, cellular, and morphological consequences. I anticipate that expression patterns of Bmps will be altered by this treatment, which will lead to facial dysmorphologies. The next two aims will elucidate the role that Bmp signaling plays during facial development. I will dissect the role of Bmp signaling within the neural crest mesenchyme and facial ectoderm by inhibiting the ability of these cells to propagate Bmp signals within the cell. Collectively, the results will allow me to determine how regionalized gene expression patterns in neural crest and ectoderm of the face are controlled by the forebrain, and will also shed light on how Bmp signals control outgrowth of the frontonasal process.