The current study is an initial molecular characterization of patterning mechanisms in the embryonic limb. The basis of this work is that the mechanisms that are utilized during normal limb formation are likely to be the same pathways utilized in regenerative responses. Therefore, by understanding the molecular basis of normal limb development we may eventually understand regenerative limb formation. The first part of this work demonstrates that the regenerative ability of mouse digit tips is restricted to levels in which the amputation plane is within the region of Msx1, but not Msx2, expression in early fetal digits and to levels where both Msx1 and Msx2 are expressed in late fetal and neonatal digits. In both fetal and neonatal digits we find that both Msx1 and Msx2 are expressed during regeneration, but not during wound healing associated with proximal amputations where no regenerative response is observed. Thus, developmental expressed genes are re-utilized during regenerative responses. Secondly, I have characterized the regulation of Sonic hedgehog when ZPA signaling tissue is grafted into the anterior or distal regions of the limb bud-prior to the formation of additional limb structures. The evidence demonstrates that Sonic hedgehog expression is AER/FGF-2/FGF-4-dependent, limited to posterior cells, and modulated by mesenchymal cell-cell interactions between host and graft cells. These data points to a novel signal within the limb mesenchyme that can modulate the ZPA signal. Finally, the characterization of the molecular changes associated with the acquisition and maintenance of ZPA-signaling in limb cells and the molecular changes associated with supernumerary digit formation from host tissues, provide interesting insights into the pathways of limb development. This study provides the first evidence indicating that ZPA-signaling can occur in the absence of Sonic hedgehog expression and moreover, that there are multiple molecular pathways to the formation of extra digit structures. Cumulatively, our results show that the mechanisms underlying limb development are very complex, but that some of the mechanisms used during limb development are re-utilized during regenerative processes / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27542 |
| Date | January 1995 |
| Contributors | Reginelli, Angela Distefano (Author), Muneoka, Ken (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
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