Thesis (M.S.)--University of Michigan, Ann Arbor, 1966. / Typescript (photocopy). eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 78-86).

Thesis (M.S.)--University of Michigan, 1997. / Includes bibliographical references.

Thesis (M.S.)--University of Michigan, 2006. / Includes bibliographical references (leaves 81-89).

Thesis--University of Denver. / Includes bibliographical references.

Thesis (doctoral)--München, 1935.

Thesis--University of Denver. / Includes bibliographical references.

Inaug.-Diss.--Königsberg. / At head of title: Aus der Chirurgischen Universitätsklinik zu Königsborg ... Lebenslauf. "Literatur": p. 25.

Thesis (doctoral)--München, 1935.

Cleft lip and palate is a developmental abnormality which affects 1 in 500 live births resulting in considerable morbidity for the affected individual and their families and providing an economic burden to the state. Human mutations in TP63 have been shown to induce at least five developmental syndromes which are characterised by the presence of orofacial clefting, malformed limbs and defects in ectoderm-derived tissues. Mouse models of Trp63 knockout display phenotypes similar to the clinical manifestation of TP63 human mutations. To date the majority of orofacial P63-related research has focussed on secondary palate development, as such the role of P63 during upper lip development remains poorly characterised. Upper lip development is similar between mouse and human. The medial nasal, lateral nasal and maxillary processes form as outgrowths of the frontonasal prominence. Directed growth of the facial processes results in their epithelial contact and adhesion. At the site of epithelial contact a double epithelial seam is formed, which must be degenerated to allow mesenchymal confluence across the upper lip. Trp63 has been shown to be expressed within the epithelia of the facial processes throughout upper lip development, with expression detected during process outgrowth, contact and adhesion. Down-regulation of Trp63 expression within the epithelial seams is followed by seam degeneration and upper lip fusion. Furthermore, the cleft lip and palate phenotype of TP63-related conditions suggests P63 plays a key role in upper lip morphogenesis. Previous studies have identified P63 target genes using high throughput methods. However, P63 functions in a tissue specific manner and so the applicability of these studies to upper lip development is hampered by their choice of model tissue. The aim of this study was therefore to identify targets of P63-regulation in upper lip development using stage appropriate tissue. High throughput methods were used to identify sites of P63 binding and genes misregulated in Trp63-/- mouse facial processes. Via characterisation of putative target genes a novel role for P63 in the regulation of Wnt and Fgf signalling during upper lip morphogenesis was identified. It is therefore suggested that during upper lip morphogenesis P63 regulates the expression of multiple members of the Wnt and Fgf signalling family to maintain the proliferative and differentiation potential of the facial processes. Furthermore regulation of Wnt and Fgf signalling provides a mechanism by which P63 may regulate epithelial to mesenchymal signalling. This project has identified potential novel targets of P63 regulation during upper lip development, in addition to providing a novel mechanism of P63 regulation of wider relevance to the embryological development of multiple tissues.

No description available.