Determination of positional identity during limb development and regeneration

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Roles of signaling molecules in determination of positional information have been studied in the developing and regenerating limb, and the results are summarized below.Wnt-5a expressed in the distal limb bud at early stage of development was over-expressed in the chick embryo using retrovirus vector, resulting in shortening of zeugopod length. Wnt family other than Wnt-3a is implicated in induction of the apical ectodermal ridge, and Wnt-10a is a candidate because of expression pattern both in the mouse and chick embryos. However, Wnt-10a was also unable to induce FGF-8 expression when misexpressed in the presumptive limb ectoderm.A novel frizzled family member, Fz-10, was identified in the chick embryo that expressed in the dorsal- posterior region of the limb mesenchyme. Fz-10 was positively regulated by both sonic hedgehog (SHH) and Wnt-7a, and shown to have an activity to mediate Wnt-7a signaling, but not Wnt-3a signaling, as demonstrated by Xenopus animal cap assay.Signaling throu … More gh GPI-anchored cell surface proteins was shown to determine proximal-distal positional value in the limb bud, as demonstrated by cell sorting assay. One of the proteins, ephrin-A2, is expressed in the proximal limb bud, whereas a receptor for ephrin-A, EphA4, is expressed in the distal limb bud with a complementary pattern. Misexpression of ephrin-A2 in the distal limb bud resulted in malformation and partial fusion of the limb cartilage within the autopod region. Limb mesenchymal cells over-expressing ephrin-A2 are segregated from non-expressing cells, suggesting involvement of ephrin-Eph interaction in position-dependent cell adhesion.SHH protein-induced digit duplication is correlated with persistent expression of HoxD12 and HoxD13, but not with transient induction of BMP-2. In the leg bud, FGF-4 could induce SHH expression in the anterior limb bud, thereby up-regulating HoxD13 expression, independent of cell migration from the body flank region. On the contrary, FGF-4 could not induce SHH expression in the wing bud, suggesting differential responsiveness to FGF signaling between the forelimb and hindlimb buds. Less