The developing limb provides an ideal model to understand how growth and pattern formation are regulated during
embryonic development. Despite recent advances, many of the mechanisms regulating limb formation are still not
understood. Gene knock-out experiments in mice have identified two genes, Tbx4 and Tbx5, that are essential for
limb development. Mice mutant for either Tbx5 or Tbx4 lack forelimbs and hindlimbs, respectively. In humans,
mutations in Tbx genes cause developmental disorders. Mutations in TBX5 are associated with Holt Oram
Syndrome (HOS) while mutations in TBX4 are associated with Small Patella Syndrome (SPS). Although these
results clearly demonstrate the importance of these proteins during limb development, little is known about their
biochemical properties and transcriptional targets.
We propose to investigate Tbx4 and Tbx5 protein function during limb development using the mouse as a model
organism. We will identify Tbx4 and Tbx5 target genes in the developing limb and investigate the mechanisms
regulating Tbx protein activity. This will greatly improve our understanding of the role of these genes during limb
development and give important insights into the molecular mechanisms underlying the aetiology of HOS and SPS
defects.