Complex functional redundancy of Tbx2 and Tbx3 in mouse limb development

Abstract

The limb phenotypes of Tbx2 and Tbx3 mutants are distinct: loss of Tbx2 results in isolated duplication of digit 4 in the hindlimb while loss of Tbx3 results in anterior polydactyly and posterior oligodactly in the forelimb. In the face of such disparate phenotypes, we sought to determine whether Tbx2 and Tbx3 have functional redundancy during development of the mouse limb. We found that sequential loss of alleles generates defects that are not simply additive of those observed in single mutants and that multiple structures in both the forelimb and hindlimb display compound sensitivity to decreased gene dosage.

TBX3 is essential for establishment of the posterior boundary of anterior genes and upregulation of posterior genes together with HAND2 during the onset of limb bud development

“…In addition, variable degrees of deltoid tuberosity agenesis, ulnar hypoplasia and thickening of the radius were detected ( Fig. 4B ; Lopatka and Moon, 2022 ). Hand2 remained expressed at lower levels in the posterior mesenchyme of Tbx3 Δ/Δc forelimb buds ( Fig.…”

“…This is relevant to limb bud development, as Tbx2 and Tbx3 are co-expressed in the anterior and posterior mesenchyme and Tbx2 expression is not altered in Tbx3 mutant limb buds (this study). Indeed, stepwise reduction of the Tbx2 and Tbx3 gene dosage increases the severity of the limb skeletal malformations, which are not strictly additive but in parts synergistic ( Lopatka and Moon, 2022 ). As the core T-box motif enriched in the TBX3 cistrome is shared by different TBX proteins, co-regulation of target genes in limb buds by several Tbx genes is likely.…”

TBX3 is essential to establish the posterior boundary of anterior genes and up-regulate posterior genes with HAND2 during onset of limb bud development

“…4B, Emechebe et al, 2016). In addition, variable degrees of agenesis of the deltoid tuberosity, ulnar hypoplasia and thickening of the radius are detected (Fig.4B, Lopatka and Moon, 2022). Hand2 remains expressed in the posterior mesenchyme of Tbx3 1/1c forelimb buds, but levels are reduced (Fig.…”

“…This could also be relevant to limb bud development, as Tbx2 and Tbx3 are co-expressed in the anterior and posterior mesenchyme and the spatial expression of Tbx2 is not altered in Tbx3 mutant limb buds (this study). Indeed, the stepwise reduction of the Tbx2 and Tbx3 gene dosage increases the severity of the limb skeletal malformations, which are not strictly additive but in parts synergistic (Lopatka and Moon, 2022). As the core sequence of the T-box motif enriched in the TBX3 cistrome is shared by different TBX proteins, coregulation of target genes by several Tbx genes expressed in limb buds is likely.…”

Limb development, evolution, and regeneration and repair: Part two

“…A study from Lin et al, 8 reminds us that the limb is not just bone and muscle to show that Keratins expression are regulated by an epigenetic switch at the cluster rather than at the single‐gene level during regional skin specification. Finally, using an allelic series resulting in progressively decreased gene dosage, Lopatka and Moon 9 show that the paralogs tbx2 and 3 have functional redundancy during development of both the forelimb and limdlimb of the mouse. Their results further show that both genes have complex, compound functions in both forelimbs and hindlimbs.…”