Figure 6: Transcriptional basis for evolution of Tbx4/5 roles in limb development.

(a) Schematic representation for divergence of an ancestral Tbx4/5 transcription factor that had activator domain (green) and for gain of repressor domain (magenta) in Tbx4. The small-patella syndrome Tbx4 mutation Q538R is within this domain. (b) The shared activator domain (green) is proposed to have an effect on limb bud growth, whereas the Tbx4 repressor domain (magenta) determines hindlimb identity. Expression of Tbx4 in hindlimbs is enhanced by Pitx1; similarly, expression of a putative co-repressor (CoR) required for Tbx4 repressor activity may be regulated by Pitx1.