Skeletal patterning in the vertebrate limb,i.e., the spatiotemporal regulation of cartilage differentiation(chondrogenesis) during embryogenesis and regeneration, is oneof the best studied examples of a multicellular developmental process.Recently [Alber et al., The morphostatic limit for a model ofskeletal pattern formation in the vertebrate limb, Bulletin ofMathematical Biology, 2008, v70, pp. 460-483], a simplified two-equationreaction-diffusion system was developed to describe the interaction of two ofthe key morphogens: the activator and an activator-dependent inhibitor ofprecartilage condensation formation. A discontinuous Galerkin (DG)finite element method was applied to solve this nonlinear system on complexdomains to study the effects of domain geometry on the pattern generated [Zhu etal., Application of Discontinuous Galerkin Methods for reaction-diffusionsystems in developmental biology, Journal of Scientific Computing, 2009, v40,pp. 391-418]. In this paper, we extend these previous results and develop a DGfinite element model in a moving and deforming domain for skeletal patternformation in the vertebrate limb. Simulations reflect the actual dynamics oflimb development and indicate the important role played by the geometryof the undifferentiated apical zone.

Retinoic acid, when administered to pregnant mice on d 11·0 of gestation, causes limb skeletal abnormalities consisting of reduced digital number, shortening of the long bones and delayed ossification. We show here that these effects are correlated with a decrease in cell proliferation within 5 h of retinoic acid administration, specifically in the posterior half of the distal limb bud mesenchyme, from which the distal skeletal elements are generated. There is a specific downregulation of Fgf4, a gene known to be involved in limb bud outgrowth and expressed only in the posterior part of the apical ectodermal ridge; Fgf8, which is expressed throughout the apical ectodermal ridge, is unaffected. The reduction in Fgf4 expression is not accompanied by downregulation of Shh, nor of its receptor and downstream target gene Ptc, suggesting that the skeletal reduction defects induced by retinoic acid are mediated specifically by FGF4-induced skeletogenic mesenchymal cell proliferation.

We report the morphogenesis of a new mouse mutant, Doublefoot (Dbf). The major phenotypic features involve the limb and craniofacial regions. There is polydactyly of all 4 limbs, with typically 6–8 digits per limb. All of the digits are triphalangeal; some show bifurcations and some are not attached to the carpus/tarsus. The carpus and tarsus are broader than normal, and their elements are partially fused. There are also tibial defects. Mutant embryos show a diencephalic bulge on d 10.0, with older animals exhibiting broadened and bulbous skulls sometimes with an additional midline skeletal element, shortened snouts and bulging eyes. Homozygotes, which do not survive beyond d 15, show midline facial clefting. In this study of the embryonic and fetal development of Dbf animals, we focus on the morphogenesis of the limbs and head, and discuss the possible molecular developmental mechanisms.

A human polydactylous left foot with 9 toes, amputated from an 11-mo-old child, was examined by x-ray and magnetic resonance imaging and by gross dissection to identify the digits. The normal sequence of toes from medial to lateral is 1, 2, 3, 4, 5. Examination of the morphology of tendons and muscles suggested the toe sequence was 1, 2, 3/4, ?,5, 2, 3/4, 3/4, 5. The 2 toes in the sequence that are underlined were displaced dorsally and were found to have 2 extensor tendons, no flexor tendons and nails that were conical and situated at their tips. These toes resembled those described as ‘double-dorsal’ and which develop in paws of mice in which a gene normally expressed ventrally is functionally inactivated (Loomis et al. 1996). Specification of toe formation occurs in leg buds early in embryonic development and later there is rotation of the limb so that the anterior (rostral) part comes to lie medially, i.e. the hallux which was anterior (rostral) now is on the inner (medial) side of the foot. A disruption in the patterning of this foot in both anteroposterior (rostral-caudal) and dorsoventral axes during development could be responsible.