description): The developing limb has been a productive model for studying pattern formation and this proposal focuses on the cascade of molecular events that establish dorsoventral asymmetry in the developing limb. Lmxlb is a homeobox gene that is critical in dorsoventral patterning during early limb development. As the limb emerges and differentiation proceeds from proximal to distal, Lmxlb is expressed in the distal undifferentiated dorsal mesoderm. In the absence of Lmxlb, the normally asymmetrical limb, develops with near ventral-ventral symmetry. The molecular interactions that initiate Lmxlb expression in the developing limb mesoderm have been partially characterized in mutant mice lacking the genes that induce Lmxlb expression. However, to complete the cascade of events that regulate dorsoventral asymmetry, genes targeted by Lmxlb must also be identified. Recently, an Lmxlb gene knockout was developed and characterized in mice. This mutant provides an excellent avenue to further delineate the molecular pathways involved in dorsoventral patterning. Several candidate genes associated with joint formation and tendon/ligament attachment (which establish joint asymmetry) are known and the expression of these genes will be compared in normal and mutant mice to identify potential genes targeted for Lmxlb regulation. In an effort to identify additional target genes, genes expressed in the dorsal limb mesoderm of mutant mice will be subtracted from normal mouse dorsal limb mesoderm. To learn how Lmxlb regulates the expression of these target genes, Lmxlb, will be expressed in ventral limb mesoderm by adenoviral vectors. It is expected that these studies will enhance our current understanding of the mechanisms that establish form and shape during development. Furthermore, it may provide additional insights into the pathogenesis of Nail-Patella Syndrome, which has been linked to mutations in the human LMXIB gene.
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