Table 1.

Summary of site and mechanism of action and clinical syndromes associated with errors in expression of principle gene families involved in limb patterning

Gene family	Example	Role	Area of action	Research	Clinical correlation
Fibroblast growth factors	FGF-4 and FGF-8	Growth factors	AER	Induce accessory limbs in chick embryos	FGF-receptor3 mutations cause achondroplasia
Hedgehog	Sonic hedgehog (Shh)	Binds Ptc to release Smo and promotes expression of BMP, WNT, HOX, & Gli	ZPA	Ectopic activity causes duplications
Patched (tumour suppressor gene) and smoothened	Ptc and Smo	Ptc is an Shh receptor. Smo is released when Shh binds Ptc.	Cell surface mesenchyme
Bone morphogenic proteins	BMP-2 BMP-7	Osteoblast differentiation Chondrocyte condensation and differentiation	Mesenchyme and AER	Digit formation and apoptosis	Hunter-Thompson and Grebe type chondrodysplasias
WNT	Wnt-7a	Dorsalising gene. Turns on LMX-1. Repressed by engrailed-1. Promotes Shh expression	AER
Fringe	Radical fringe	Limits the AER to the tip of the limb bud	Dorsal AER
Homeobox (HOXA, B, C, D)	Hox-b8	Controls limb positioning and patterning in developing zeugopod, autopod and stylopod	Overlapped pattern in lateral plate mesoderm and limb bud		Hand-foot-genital syndrome Synpolydactyly
T-box	Tbx4 Tbx5	Transcription factors, turned on by BMP2, BMP4 or Wnt, control limb identity	Early stages of limb outgrowth	Mis-expression changes limb morphology from forelimb to hindlimb or vice versa	Holt-Oram syndrome
SOX	SOX9	Condensation and differentiation of chondroblasts	Early skeleton		Campomelic dysplasia