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.
Limb abnormalities are one of the more frequent human birth defects which together affect ~ 3% of all infants born in the US. The presence of a major birth defect in a newborn will frequently reduce the quality of life for both the child and the parents. In this context limb defects are often one aspect of a more complex pathology that might also impact the heart, face, or body wall because many developmental systems rely on a common set of genes for morphogenesis and patterning. The limb is a very amenable experimental system to understand the complex interaction of these genes in the regulation of organogenesis during the development of an embryo. The limb is also a powerful model to study tissue and organ regeneration and knowledge of the signaling mechanisms required for limb outgrowth will be key to understanding how regrowth of a limb can eventually be achieved in the clinic.
