Papangeli, I.; (2010) Tbx1: potential targets and interactors relevant to development of structures affected in DiGeorge Syndrome. Doctoral thesis , UCL (University College London).

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Abstract

22q11DS is the most common microdeletion syndrome in humans, causing a range of phenotypes associated with abnormal pharyngeal development. TBX1 is considered the major genetic determinant of the syndrome. Deletion of Tbx1 in animal models phenocopies the patient manifestations. In an effort to understand the pathways involved in these processes, potential Tbx1 effectors previously determined by microarray screens were studied. Smad7 is an inhibitor of the TGF-/BMP pathways and to date several TGF-/BMP signalling genes have been described in heart development. In this thesis Smad7 was found expressed in pharyngeal and cardiovascular structures during mouse embryogenesis while a gene-trap mouse model displayed a partially penetrant 22q11DS-like phenotype. Furthermore, Tbx1 and Smad7 were found to interact synergistically towards arch artery morphogenesis. Hes1 is a transcriptional repressor, part of the Notch signalling pathway, which produces craniofacial and cardiovascular anomalies when deactivated. Expression analysis undertaken demonstrated that Hes1 overlaps with Tbx1 in the embryonic pharynx and it is diminished in Tbx1-/- embryos. A conditional mutagenesis approach revealed non cell autonomous actions for Hes1 in the ectoderm affecting great vessel and eye development, while Hes1 was required in both the ectodermal and neural crest lineages for thymus morphogenesis. Slit2 is a secreted protein that regulates axonal guidance, migration, outgrowth and branching. Recent evidence suggests a possible mechanism by which Tbx1 may regulate neural crest patterning through the Slit/Robo pathway. Slit1 and Slit2 were here shown to share expression domains with Tbx1 in the embryonic pharynx. Nevertheless, neither the Slit2 nor the Slit1;Slit2 mutation produced a 22q11DS-like phenotype while double mutation for Tbx1;Slit2 did not enhance the Tbx1 haploinsufficient phenotype. Altogether, this thesis provides data clarifying a subset of Tbx1 mechanisms important for cardiovascular development and identifies Smad7 as a Tbx1 regulated gene involved in great vessel morphogenesis.

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