T-box Genes in Limb Development and Disease

Rallis, Charalampos (2004). T-box Genes in Limb Development and Disease. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fa0b

Abstract

T-box genes comprise an ancient family of transcriptional regulators with important functions during development. The aim of this study is to investigate the roles of two closely related T-box genes Tbx5 and Tbx3 in limb development using the mouse and chick embryo as model organisms. These genes are physically linked in the genome, and human mutations in TbX5 and TbX3 lead to congenital diseases.
Tbx5, is expressed in the forelimb but not in the hindlimb of the developing vertebrate embryo and has been proposed to have a role in limb-type specification. However, Tbx5 is also required for normal limb development since haploinsufficiency of TBX5 in human causes Holt-Oram Syndrome (HOS), a dominant disorder characterized by fore(upper) limb deformities and heart defects. I have taken two approaches to investigate the role of Tbx5 in limb- type specification and outgrowth. The first is a conditional knock-out method in the mouse where I inactivated Tbx5 specifically in the developing forelimbs. As a complementary strategy I injected dominant-negative and dominant-active forms of Tbx5 in the developing chicken wing using replication-competent avian retroviruses. My results from the mouse, suggest that Tbx5 has a vital role during early limb formation. In addition, my data using the chicken retroviral system establish a role for Tbx5 in later limb patterning events and provide an insight into understanding the genesis of HOS deformities in man.