116 Ridge FGFs not only keep mesodermal cells proliferating. The role of FGFs in regulating cell death is shown by Dudley et al. (2002). See Zou and Niswander (1996) for the role of cell death in eliminating inter-digital webbing in chickens but not ducks. Webbing in humans, more precisely syndactyly, is sometimes the result of an excess of FGF signalling caused by gain-of-function mutations in the FGF receptor, FGFR2, as in Apert syndrome (101200; 176943) (Wilkie et al. 1995).
118 This account of the making of our limbs. The role of thalidomide in phocomelia was first reported by McBride (1961) and Lenz (1962). Phocomelia appears in Roberts’s syndrome (268300) and SC Phocomelia syndrome A (269000), which may be the same disorder and are known as ‘pseudothalidomide’ syndromes; the genetic basis of neither is known. Goya’s sketch of a phocomelic infant is in the Louvre; Vrolik (1844–49) depicts Pepin; a brief account of his life is given in Gould and Pyle (1897) p.263.
120 How does thalidomide have its devastating effects? Stephens et al. (2000) reviews some of the voluminous literature on thalidomide. He firmly discounts recent sensationalistic claims that thalidomide-induced phocomelics (who are now in their late thirties) are giving birth to phocomelic children – which, if true, would imply the existence of some form of Lamarkian inheritance. In principle, however, thalidomide might be a general mutagen causing high frequencies of all sorts of genetic disorders in second-generation infants. Exhaustive studies have failed to show that this is so. Until recently, the best account of the action of thalidomide on limb formation was given by Tabin (1998). His explanation, which he convincingly defended against others (Neubert et al. 1999; Tabin 1999), rested on the idea that thalidomide causes a disassociation between proliferation and proximal-distal specification of limb-buds. In other words, it was couched in terms of the ‘Progress Zone’ model of limb specification. With the demise of that model (Sun et al. 2002; Dudley et al. 2002) the specificity of thalidomide becomes a little more difficult to explain but still probably depends on the abnormal inhibition of proliferation in particular populations of bone-precursors. It is striking that FGF8-conditional limb mutants in mice have phocomelia (Lewandoski et al. 2000; Moon and Capecchi 2000).
121 Metric, with its base 10 units. Until recently it was held that all modern vertebrates (living or not) have no more than five digits (Shubin et al. 1997). True, some creatures such as pandas and moles appeared to have six, but they could be dismissed as not being true fingers, but rather modified wrist bones (the radial sesamoid in pandas and falciform bone in moles). Polydactyly can, however, evolve in flippers such as the paddles of the icthyosaur, Opthalmosaurus, which appear to conceal eight digits (Hinchliffe and Johnson 1980 p.56), and those of the vaquita dolphin, which have six (Ortega-Ortiz and Villa-Ramirez 2000). Alberch (1986) discusses polydactylous dogs; Lloyd (1986) does so for cats; and Wright (1935) for guinea pigs. Galis (2001) reviews the question of why, despite the frequency of polydactylous mutations, so few species exist with more than five digits per limb. Polydactly in humans (603596) and many other entries). Frequencies and kinds of Polydactyly from Flatt (1994); in the Ruhe family (Glass 1947); in the Scipion family (Manoiloff 1931).
122 If the apical ectodermal ridge. For the discovery of the zone of polarising activity see Saunders and Gasseling (1968); for its interpretation see Tickle et al. (1975). Sonic hedgehog (600725) was first identified as the gene encoding the morphogen by Riddle et al. (1993). Since then, some (Yang et al. 1997) have argued that it is not the morphogen since it does not form a gradient in the limb. More recent evidence suggests that it does (Zeng et al. 2001).
126 This catalogue of mutations. Many polydactyly genes have been identified in mice and humans, and many are transcription factors. For example, mutations in GH3 (165240), a zinc-finger transcription factor, cause Greig’s cephalopolysyndactyly (175700), Pallister-Hall syndrome (146150) and postaxial polydactyly (174200; 174700). See Manouvrier-Hanu et al. (1999) for a brief review of others. On-line Mendelian Inheritance in Man (August 2002) lists ninety-seven disorders with polydactyly in the clinical synopsis. How many of these are genuinely different is an interesting question, but the suggestion is certainly that more than ten genes are involved in correctly determining Shh activity. The Shh regulatory mutation causes extra thumbs and index fingers, more broadly, preaxial polydactyly (190605; 174500). The genetics are complicated. Zguricas et al. (1999) mapped the mutations, deletions and translocations to 7q36, close to the Shh gene. Clark et al. (2001) showed that these mutations deleted a portion of Lmbri (605522), a gene near sonic hedgehog, and inferred that Lmbri was causal. Lettice et al. (2002), whose interpretation I follow here, provide evidence that 7q36 Polydactyly mutations are due to deletions of sonic hedgehog cis-acting regulatory elements that lie within a Lmbri intron rather than Lmbri itself. Achieropody (200500), which also maps to 7q36, has a similarly complex history. Achieropody mutations also delete Lmbri and, again, this gene was thought to be causal (Ianakiev et al. 2001; Clark et al. 2001), but is also probably due to a Shh regulatory mutation – though the jury is still out (Lettice et al. 2002). Certainly, the similarity of acheiropody to the pawless limbs of Shh-null mice is striking (Chiang et al. 1996; Chiang et al. 2001).
127 Around day 32 after conception. For the gross development of the human limb see Hinchliffe and Johnson (1980) p.75 and Ferretti and Tickle (1997). The condensations are described by Shubin and Alberch (1986). For a Hoxa13 mutation in man causing hand-foot-genital syndrome, (142959; 140000) see Mortlock and Innes (1997). Mouse models: Fromental-Ramain et al. (1996) and Mortlock et al. (1996). For a Hoxan mutation causing radioulnar systosis (142958; 605432) see Thompson and Nguyen (2000); Hoxd13 (gain of function) (142989), Muragaki et al. (1996); Hoxd cluster deletion, Del Campo et al. (1999). For the most comprehensive attempt at determining what the Hox genes are doing in the limb see Zákány et al. (1997), who report the effects of knocking out a variety of Hoxa and Hoxd genes in combination.
128 Limbs are not the only appendages. For Hox mutations that cause both limb and genital defects in humans see the preceeding note and Kondo et al. (1997). Penis size and foot length (Siminoski and Bain, 1993). For the roles of FGFs and sonic hedgehog in genitals see Perriton et al. (2002) and Haraguchi et al. (2000).
131 The result is rather puzzling. On the homology of lobe-finned fish fins to tetrapod limbs see Shubin et al. (1997) for a review. Sordino et al. (1995) describe Hox gene expression patterns in zebrafish compared to tetrapods. Cohn and Bright (2000) review zebrafish fin development. Dollé et al. (1993) report the Hox d13 knockout in mice; Zákány et al. (1997) argue for the successive accretion of Hox genes in evolution. The first edition of Darwin’s The variation of animals and vegetables under domestication was published in 1868; Gegenbauer’s critique in 1880. The Darwin quote is from the second (1882) edition of The variation pp.457–8 where he retreats. Coates and Clack (1990) describe Acanthostega’s limbs.