What happens in TBX5-null mice?
Tbx5 null embryos fail to activate forelimb gene regulatory network causing selective agenesis. Normally TBX5 in rostral lateral plate mesoderm activates FGF10 transcription, initiating Wnt2b, Wnt3a and FGF8 cascades and AER formation through beta-catenin. In absence of TBX5, FGF10 not induced, Wnt cascades fail, no AER forms, thus no forelimb bud emerges while hindlimbs remain intact because they depend on Pitx1 Tbx4 axis independent of Tbx5. Digits not independently lost since entire forelimb absent, mirroring human Holt-Oram syndrome where TBX5 haploinsufficiency causes forelimb anomalies including thumb defects. Phenotype demonstrates essentiality of TBX5 for forelimb initiation.
Ref: Ahn et al., Development 2002, Gilbert Chapter 20: TBX5-null forelimb agenesis phenotype.