The development and patterning of an embryo requires coordinate interactions between different tissue layers at appropriate times for successful outcome. Mechanistically, this is driven by a group of conserved signaling molecules, their receptors, and their downstream transcriptional effectors. Disruptions of these molecules and their signaling processes can lead to birth defects and/or pregnancy loss. Although many birth defects have clear environmental and genetic causes, insufficient information exists concerning the mechanisms of development to enable the majority of these defects to be detected or prevented pre-natally. An important goal is to develop animal models of congenital malformations that will lead to mechanistic insight into the diagnosis and treatment of related human birth defects. The process of mammalian limb induction, outgrowth and patterning is a pertinent model that can be used to investigate multiple aspects of development and signaling. The development of the limb relies on reciprocal signaling between celln exists concerning the mechanisms of development to enable the majority of these defects to be detected or prevented pre-natally. An important goal is to develop animal models of congenital malformations that will lead to mechanistic insight into the diagnosis and treatme upregulation of canonical Wnt signaling in the early mouse embryonic ectoderm via the stabilization of -catenin greatly upregulates Fgf8 expression. The consequences of these molecular changes are that limb formation is induced along the entire lateral axis between the forelimb and hindlimb buds. This leads to the appearance of a "unilimb" structure that generates a mechanical constraint on normal axis elongation in the mouse trunk. Two hypotheses were generated by these observations: (1) the up-regulation of Fgf8 is responsible forlls expressing factors belonging to the Fgf family of secreted molecules, especially Fgf8 and Fgf10. Further evidence has implicated another signaling pathway, involving Wnt proteins and -catenin, in two crucial events during limb development. First, the canonical Wnt signaling pathway is needed for establishment of the initial domain of Fgf10 expression. Second, this pathway is required for formation of the apical ectodermal ridge (AER), which is a major organizing center for limb outgrowth and patterning. Recent evidence indicates that the upregulation of canonical Wnt signaling in the early mouse embryonic ectoderm via the stabilization of -catenin greatly upregulates Fgf8 expression. The consequences of these molecuom this R01 application.

R01HD060882

2009-07-17

2012-06-30