Francis, J.C.; (2006) The role of Notch1 and vestigial-like1 in vertebrate limb development. Doctoral thesis , University of London.

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Abstract

Comparative studies of Drosophila genes and their vertebrate orthologues have shown that they can play analogous roles during embryonic development. Good examples are found during the development of the Drosophila wing, which can be considered analogous to the vertebrate limb. The Drosophila melanogaster genes vestigial and Notch are essential for proximal-distal outgrowth of the wing. I have investigated whether vertebrate orthologues, Vestigial-like I (Vgll) and Notchl, respectively, are involved in vertebrate limb development. In the fly, Notch signalling at the dorsoventral boundary of the wing activates downstream targets, such as vestigial and wingless. Similarly, vertebrate Notchl is expressed in a specialised region of cells at the dorsoventral boundary of the limb, the apical ectodermal ridge (AER). Classical embryological studies and genetic manipulation has demonstrated that the AER is required for proximal-distal outgrowth of the vertebrate limb. However, the role of Notchl in the vertebrate limb is poorly understood since the conventional knockout of Notchl dies before the onset of limb development. I have used a conditional allele of Notchl and exploited Cre/lox technology to delete Notchl function in either the ectoderm or mesenchyme of the developing limb. My results demonstrate that Notchl is required to regulate the size of the AER, but is not required for the development of any of the mesenchyme derivatives. Genetic studies in the fly have shown that vestigial is necessary and sufficient for wing morphogenesis. I have shown that chick Vgll is expressed in a subpopulation of ectoderm cells, the periderm. Misexpression of various forms of Vgll in the developing chick limb, using the chick retroviral system, has revealed a potential role for Vgll and the periderm in the formation of the AER.

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