Cell Signaling Regulation of Vertebrate Limb Growth and Patterning

Abstract

Limb development is a well-coordinated three-dimensional process in which limb-bud outgrowth and patterning along the different axes of development are intimately linked through interactions of the signaling molecules that mediate the function of three key signaling centers. The vertebrate limb develops from a primordial embryonic limb bud, consisting of a homogeneous mesoderm core covered by an ectodermal jacket, and development of the limb bud is an autonomous process controlled by these signaling centers, which are formed through epithelial-mesenchymal interactions. The major signaling centers in the limb each direct limb development along one of the three axes: proximodistal (from shoulder to digit tip), anteroposterior (from digit 1, or thumb, to digit 5, or small finger) and dorsoventral (from the dorsum to the palm of the hand) (Table I). View this table: TABLE I Signaling Pathways During Embryogenesis These signaling centers were identified by classic embryological experiments; recent molecular genetic studies in both the mouse and the chick have revealed signaling molecules that mediate the functions of these centers1. Although they only act early in the limb bud, these signaling centers have a profound influence on limb morphology by providing positional cues that determine the shape and spatial organization, as well as the temporal order of formation, of limb structures such as bones and tendons. We will describe several of the known links between the different development axes and give examples of the ways in which genetic mutations or disrupted embryonic development can affect these signaling events and cause longitudinal deficiencies and other malformations in humans and in mouse genetic mutants. The first signaling center to appear is the apical ectodermal ridge (AER), which is a thickened epithelial structure at the distal tip of the limb bud. In human embryos, limb initiation occurs at twenty-six days post coitum; in the mouse, the limb bud …