Primates display considerable differences in their limb proportions and skeletal morphologies. Part of this variation arises from selection acting on embryonic developmental control mechanisms governing limb patterning and morphogenesis. As Hox genes are critical regulators of these processes in the limb, it is believed that changes in their embryonic cis- and trans-regulation underlie many of the morphological differences observed across primates. A major aspect of Hox involvement in limb patterning revolves around their ability to target numerous other genes, and part of their DNA binding specificity is achieved through their interaction with cofactors. One such group of cofactors is the Pre-B Cell Luekemic Factor (Pbx) gene family ( Pbx1-4). Using compound mutant mice that harbor critical gene deletions for several Pbx members, this study examines how the simultaneous loss of multiple Pbx genes impacts limb development and skeletal patterning. It is shown that limb and axial morphologies that derive from domains where multiple Pbx overlap are more severely affected in compound mutants, than when individual Pbx family members are lost in these domains, suggesting a multigenic control of skeletal patterning by Pbx. Importantly, it is demonstrated that Pbx controls Hox expression in the limb, and therefore regulates limb patterning along the entire proximodistal axis. Pbx genes are also shown to regulate Sonic hedgehog expression, a gene essential for distal limb and digit development. Interestingly, it is also shown that Pbx functions predominately in the early limb field, as conditional inactivation of Pbx in mouse embryos after limb bud establishment results in normal limb patterning. Finally, Pbx genes also are shown to lie upstream of most genes involved in girdle patterning and therefore, play critical roles in coordinating development of the entire functional appendage. Pbx participation in many genetic networks involved in limb and girdle development reveals that their modulation can provide an evolutionary mechanism to coordinate morphological change in the limb across multiple developmental and functional domains. In this manner, this thesis explores how variation in primate limb proportionalities could have arisen by modulation of a specific Pbx-Hox-Shh developmental network during limb development.
|School||CITY UNIVERSITY OF NEW YORK|
|Subjects||Molecular biology; Physical anthropology; Genetics|
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