Interactions between dorsal-ventral patterning genes lmx1b, engrailed-1 and wnt-7a in the vertebrate limb

Abstract

The vertebrate limb has characteristic morphological features that distinguish dorsal and ventral regions. For example, humans and most other mammals have nails on the dorsal surface of their digits, while the ventral surface is covered by skin or footpads. Internally, there is a high degree of organization along the dorsal-ventral axis. Extensor muscles are generally located dorsally while flexor muscles are generally located ventrally. The skeleton has subtle differences that allow for attachment of these muscles and distinct pools of motor neurons innervate either dorsal or ventral muscles. How is this complex arrangement of tissues generated? Recent studies have identified a molecular cascade of three factors that govern early events in dorsal-ventral limb patterning. Two of these factors, engrailed-1 and wnt-7a are expressed in the dorsal and ventral ectoderm respectively. The function of engrailed-1 is to repress the expression of wnt-7a in the ventral limb bud ectoderm. The third factor, a LIM-homeodomain transcription factor, lmx1b is induced in dorsal mesenchyme by wnt-7a and it is both necessary and sufficient to specify dorsal limb pattern. In this report, we examine genetic interactions between wnt-7a, engrailed-l, and lmx1b by analyzing the phenotypes of mice that are double mutants for lmx1b and either wnt-7a or engrailed-1. These studies indicate that lmx1b is the only target of wnt-7a and engrailed-1 that is of consequence for dorsal-ventral patterning. Moreover, this genetic analysis suggests that lmx1b plays additional roles in anterior-posterior patterning and growth that were not previously appreciated.