Harvey, S.A.; (2006) The role of SALL4 in vertebrate limb development. Doctoral thesis , University of London.

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Abstract

Genes required for limb development have, in several instances, first been identified by studies of human diseases in which the limbs are affected. In humans, mutations in the transcription factor SALL4 results in Okihiro syndrome (OS), which is characterised by forelimb defects and the eye disorder, Duane anomaly. OS patients forelimb defects range from subtle thumb abnormalities to truncated limbs. Mutations in another gene, TBX5, cause Holt-Oram syndrome (HOS), which is defined by heart and forelimb defects. OS and HOS patients limb defects are very similar, in fact, patients that have mutations in SALL4, and thus OS, have in some cases been misdiagnosed with HOS. Studies have shown that Tbx5 performs an evolutionary conserved role in forelimb development. The similar limb phenotypes of OS and HOS patients may suggest that Tbx5 and Sall4 act in a common pathway and that Sall4 is also required for forelimb development. During my thesis work, I have investigated the function of Sall4 and I have explored the hypothetical relationship between Sall4 and Tbx5 during limb development. To perform this analysis I have used zebrafish, chick and mouse model systems. I demonstrate that in the developing zebrafish pectoral fins sall4 acts downstream of tbx5, and that sall4 is essential for pectoral fin (forelimb) development. I show that tbx5 initiates a feedforward transcriptional motif that is required to establish FGF signalling in the pectoral fin bud. My studies of sail gene family redundancy and tbx5 offer explanations for the similarity of OS and HOS patients limb defects.

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