Limb development

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb. Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb. Limb formation begins in the morphogenetic limb field, as mesenchymal cells from the lateral plate mesoderm proliferate to the point that they cause the ectoderm above to bulge out, forming a limb bud. Fibroblast growth factor (FGF) induces the formation of an organizer at the end of the limb bud, called the apical ectodermal ridge (AER), which guides further development and controls cell death. Programmed cell death is necessary to eliminate webbing between digits. The limb field is a region specified by expression of certain Hox genes, a subset of homeotic genes, and T-box transcription factors – Tbx5 for forelimb or wing development, and Tbx4 for leg or hindlimb development. Establishment of the forelimb field (but not hindlimb field) requires retinoic acid signaling in the developing trunk of the embryo from which the limb buds emerge. Also, although excess retinoic acid can alter limb patterning by ectopically activating Shh or Meis1/Meis2 expression, genetic studies in mouse that eliminate retinoic acid synthesis have shown that RA is not required for limb patterning. The limb bud remains active throughout much of limb development as it stimulates the creation and positive feedback retention of two signaling regions: the AER and its subsequent creation of the zone of polarizing activity (ZPA) with the mesenchymal cells. In addition to the dorsal-ventral axis created by the ectodermal expression of competitive Wnt7a and BMP signals respectively, these AER and ZPA signaling centers are crucial to the proper formation of a limb that is correctly oriented with its corresponding axial polarity in the developing organism. Because these signaling systems reciprocally sustain each other’s activity, limb development is essentially autonomous after these signaling regions have been established. Limb formation begins in the morphogenetic limb field. Limb formation results from a series of epithelial-mesenchymal inductions between the mesenchymal cells of the lateral plate mesoderm and the overlying ectodermal cells. Cells from the lateral plate mesoderm and the myotome migrate to the limb field and proliferate to the point that they cause the ectoderm above to bulge out, forming the limb bud. The lateral plate cells produce the cartilaginous and skeletal portions of the limb while the myotome cells produce the muscle components. The lateral plate mesodermal cells secrete fibroblast growth factors (FGF7 and FGF10) to induce the overlying ectoderm to form an organizer at the end of the limb bud, called the apical ectodermal ridge (AER), which guides further development and controls cell death. The AER secretes further growth factors FGF8 and FGF4 which maintain the FGF10 signal and induce proliferation in the mesoderm. The position of FGF10 expression is regulated by two Wnt signaling pathways: Wnt8c in the hindlimb and Wnt2b in the forelimb. The forelimb and the hindlimb are specified by their position along the anterior/posterior axis and possibly by two transcription factors: Tbx5 and Tbx4, respectively. The limb's skeletal elements are prefigured by tight aggregates known as cellular condensations of the pre-cartilage mesenchymal cells. Mesenchymal condensation is mediated by extracellular matrix and cell adhesion molecules. In the process of chondrogenesis, chondrocytes differentiate from the condensations to form cartilage, giving rise to the skeletal primordia. In the development of most vertebrate limbs (though not in some amphibians), the cartilage skeleton is replaced by bone later in development. The limb is organized into three regions: stylopod, zeugopod, and autopod (in order from proximal to distal). The zeugopod and the autopod contain a number of periodic and quasi-periodic pattern motifs. The zeugopod consists of two parallel elements along the anteroposterior axis and the autopod contains 3-5 (in most cases) elements along the same axis. The digits also have a quasi-periodic arrangement along the proximodistal axis, consisting of tandem chains of skeletal elements. The generation of the basic limb plan during development results from the patterning of the mesenchyme by an interplay of factors that promote precartilage condensation and factors that inhibit it.