[Molecular mechanism of limb muscle patterning]

Pattern formation of the limb muscles involves a network between intrinsic programs of gene expression in myogenic precursor cells and extrinsic signals derived from the surrounding tissue. The cells at the lateral edge of the somite are specified to the precursors of the hypaxial muscles by intercelluler interaction with the dorsal ectoderm and the lateral mesoderm. At the level of the limb bud, these premyogenic cells expressing c-MET and Pax-3 are induced to invade into the limb bud by HGF/SF and unknown chemotactic signal(s) exerted by the limb mesenchyme. It is likely that N-cadherin and some extracellular matrixes are involved in this phenomena. In the limb bud, myogenic cells proliferate under influence of the limb ectoderm and congregate into the premuscle masses. BMPs expressed in limb ectoderm may maintain the proliferative phase of the myogenic cells by inhibition of the myogenic differentiation. Recently, detailed analysis of expression of Hox genes in the chick limb musculature suggests that Hoxa-11 and Hoxa-13 autonomously regulate the pattern formation of the limb muscles. Hoxa-11 is induced in the myogenic cells by an interaction with the limb mesenchyme as soon as they invade into the limb. It is possible that Hoxa-11 may confer a limb-specific property on these myogenic cells. After the formations of muscle masses, Hoxa-11 and Hoxa-13 are expressed in the muscle masses in region-specific manner along the anteroposterior and proximodistal axes under the control of the limb mesenchyme and the polarizing signal(s). They are candidates for intrinsic regulator of myogenic cells that control 1) the splitting processes of the muscle masses and 2) the specification of each muscle.