Experimental evidence indicates that the mandibular primordia are specified as at least two independent functional regions: two large lateral (proximal) regions where morphogenesis is dependent on FGF8 signaling, and a small medial region where morphogenesis is independent of FGF8 and dependent on other signals. Based on their patterns of expression, multiple signaling molecules secreted by the epithelium in the medial region including ET-1, FGFs (other than FGF8), and BMPs are involved in morphogenesis of the medial region. Furthermore the expression of a number of regulatory genes in the highly proliferative mesenchyme in the medial region suggests that the regulatory hierarchies controlling morphogenesis of the medial region of the developing mandible are complex and involve multiple pathways. However, it is currently unclear how many signaling pathways regulate the development of this region. Recent genetic studies indicate that the """"""""ET-1-dHAND-Msx1 pathway"""""""" constitutes one of the genetic pathways involved in outgrowth and morphogenesis of the medial region. The experiments in this proposal focus on understanding the regulatory hierarchies controlling morphogenesis of the medial region that are dependent on or regulated by FGF- and BMP- mediated pathways. Specific in vivo and in vitro experiments are proposed to test the following hypotheses: 1) the proliferative mesenchyme of the medial region, in addition to giving rise to outgrowth, participates in elongation of Meckel's cartilage. 2) The availability and maintenance of the proliferative mesenchyme in the medial region are in part regulated by FGF-mediated pathways. FGFs secreted by the epithelium and mesenchyme of the medial region, through their interactions with FGFR2b and FGFR2c, are part of the signaling pathways that mediate the growth- promoting interactions and maintain the proliferation of the undifferentiated mesenchyme in the medial region. 3) The lateral to medial elongation of Meckel's cartilage that leads to the formation of its symphysial portion is in part regulated by a BMP-mediated pathway. 4) Prx1 and Prx2 gene products are downstream targets of the FGF mediated pathway in the medial region that regulates outgrowth. 5) Later in mandibular development Prx1 and Prx2 play essential roles in perichondrium- mediated appositional growth of Meckel's cartilage.
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