As candidates for genes that are involved in shaping our arms (forelimbs) and legs (hindlimbs) we have previously isolated members of a family of evolutionary conserved, so called T-box transcription factors. The forelimb-specific Tbx5 and the hindlimb-specific Tbx4 genes appear to be important in limb initiation and outgrowth as well as limb-type specification and are currently the main focus of our work. When mutated in humans, both genes cause severe birth defects characterized by upper limb and heart septation defects (Holt-Oram Syndrome) or patella, hip, and foot malformations (Small Patella Syndrome), respectively.
Employing chicken developing limb buds we have recently identified proteins that physically interact with the Tbx5 transcription factor. One of these proteins is a new member of the PDZ-LIM protein family that binds specifically to either Tbx5 or Tbx4 and inferring from the proteinís expression patterns, it is expected to have a function in limb and heart development. Our biochemical and cell biology studies suggest that this PDZ-LIM protein links the Tbx4/5 transcription factors to intracellular signaling pathways. The discovery of Tbx protein-protein interactions is a first inroad towards the understanding of Tbx transcription factor regulatory networks, and it provides new insights into common pathways that are active in the limbs and heart.
The laboratory is using a range of molecular techniques to clone and engineer genes, retroviral gene transfer techniques for functionally testing them in vivo; biochemical techniques to determine the encoded protein structure and function, and cell biological techniques to visualize subcellular localizations of mRNA and protein.