RESUMO
Of vertebrate organ systems, the developing limb has been especially well characterized. Morphological studies have yielded a wealth of information describing limb outgrowth and have allowed for the identification of a multitude of important factors. In terms of the latter, key signaling pathways are known to control numerous aspects of limb development, including establishment of the early limb field, determination of limb identity, elongation of the limb bud, specification of digit pattern, and sculpting of the digits. Modification of underlying signaling pathways can thus result in dramatic alterations of the limb phenotype, accounting for many of the diverse limb patterns observed in nature. Given this, it is clear that signaling pathways regulate the highly orchestrated and tightly controlled sequence of cellular events necessary for limb outgrowth; however, exactly how molecular signals interface with the cell biology of limb development remains largely a mystery. In this review we first provide an overview of a number of the morphogenetic signaling pathways that have been identified in the developing limb and then review how a subset of these signals are known to modify cell behaviors important for limb outgrowth.
Assuntos
Padronização Corporal/genética , Embrião de Mamíferos/embriologia , Embrião não Mamífero , Extremidades/embriologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Transdução de Sinais/genética , Animais , Apoptose/fisiologia , Comunicação Celular/genética , Divisão Celular/genética , Movimento Celular/genética , Ectoderma/citologia , Ectoderma/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Extremidades/anatomia & histologia , Extremidades/fisiologia , Dedos/embriologia , Dedos do Pé/embriologiaRESUMO
Much of what we currently know about digit morphogenesis during limb development is deduced from embryonic studies in the chick. In this study, we used ex utero surgical procedures to study digit morphogenesis during mouse embryogenesis. Our studies reveal some similarities; however, we have found considerable differences in how the chick and the mouse autopods respond to experimentation. First, we are not able to induce ectopic digit formation from interdigital cells as a result of wounding or TGFbeta-1 application in the mouse, in contrast to what is observed in the chick. Second, FGF4, which inhibits the formation of ectopic digits in the chick, induces a digit bifurcation response in the mouse. We demonstrate with cell marking studies that this bifurcation response results from a reorganization of the prechondrogenic tip of the digit rudiment. The FGF4 effect on digit morphogenesis correlates with changes in the expression of a number of genes, including Msx1, Igf2, and the posterior members of the HoxD cluster. In addition, the bifurcation response is digit-specific, being restricted to digit IV. We propose that FGF4 is an endogenous signal essential for skeletal branching morphogenesis in the mouse. This work stresses the existence of major differences between the chick and the mouse in how digit morphogenesis is regulated and is thus consistent with the view that vertebrate digit evolution is a relatively recent event. Finally, we discuss the relationship between the digit IV bifurcation restriction and the placement of the metapterygial axis in the evolution of the tetrapod limb.
Assuntos
Extremidades/embriologia , Fatores de Crescimento de Fibroblastos/farmacologia , Proteínas Proto-Oncogênicas/farmacologia , Fatores de Transcrição , Animais , Apoptose/efeitos dos fármacos , Evolução Biológica , Padronização Corporal/efeitos dos fármacos , Padronização Corporal/genética , Padronização Corporal/fisiologia , Cartilagem/citologia , Cartilagem/efeitos dos fármacos , Cartilagem/embriologia , Divisão Celular/efeitos dos fármacos , Embrião de Galinha , Feminino , Fator 4 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Genes Homeobox/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Hibridização In Situ , Fator de Crescimento Insulin-Like II/genética , Deformidades Congênitas dos Membros/induzido quimicamente , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/genética , Fator de Transcrição MSX1 , Camundongos , Morfogênese , Gravidez , Proteínas Proto-Oncogênicas/fisiologia , Transdução de Sinais , Especificidade da EspécieRESUMO
The effects of Bmp-4 on interdigital cell death were investigated in the mouse. Affi-Gel beads, loaded with recombinant Bmp-4 protein, were transplanted into the interdigital tissues of day 12.5 hindlimb, ex utero. It was established that Bmp-4 could induce precocious interdigital cell death. Using in situ hybridization, the expression patterns of bmp-4 and alk-6 receptor were established. Both genes were found coexpressed in the interdigital region of 12.5- and 13. 5-day hindlimbs. This suggests that Bmp-4 may act in an autocrine fashion. We have also studied the effects of Bmp-4 on 12.5-day interdigital tissue cultures. In all specimens examined, the interdigital tissues produced cartilage instead of participating in cell death. The addition of exogenous Bmp-4 to the interdigital cultures did not induce apoptosis but instead enhanced chondrogenesis. The discrepancy between the effects of Bmp-4 in vitro and ex utero was attributed to the presence of digits. When a flanking digit was left attached to the interdigital tissues, in vitro, Bmp-4 promoted apoptosis instead of chondrogenesis. In sum, the results suggest that Bmp-4 is a multifunctional protein and its effect on the interdigital tissues is dependent on the modulating influence of the digits.