Wnt-signaling and skeletogenesis.

Members of the Wnt gene family, encoding secreted cystein-rich glycoproteins, have been isolated from a variety of organisms. They serve as important developmental signaling molecules and have been implicated to play crucial roles in such diverse processes as cancer, organogenesis and pattern formation. Experiments by Zakany and Duboule, and Rudnicki and Brown have suggested a role for Wnt molecules in negatively regulating chondrogenesis. However, neither of the two Wnt genes used in these studies is endogenously expressed in chondrogenic regions. We and others have found that in the chick limb at least four members of the Wnt gene family, Wnt-4, Wnt-5a, Wnt-5b, and Wnt-14, are expressed in defined regions of the developing chondrogenic elements. With the exception of Wnt-5b, which is expressed in perichondrial cells and prehypertrophic chondrocytes, the expression of the three other Wnt genes is restricted to the perichondrium surrounding the cartilage element. Viral misexpression studies in the chick suggested that Wnt-4 acts as a positive signal originating from the joint region and when misexpressed accelerates chondrocyte maturation, while Wnt-5a and Wnt-5b both negatively regulate chondrocyte maturation. We have further shown that they utilize different signaling pathways; while Wnt-4 signals through the canonical Wnt-pathway, Wnt-5a and Wnt-5b do not. Interestingly, the delay in chondrocyte maturation due to Wnt-5a misexpression is associated with an up regulation of Wnt-5b expression in the prehypertropic chondrocytes. Concomitantly, Wnt-5b misexpression also delays chondrocyte maturation. However, preliminary studies suggest that the two Wnt genes affect different steps in the maturation process. Wnt signaling, however, is not only regulating chondrogenesis but is also involved in the segmentation process of the appendicular skeleton. Localized misexpression of the fourth Wnt gene, Wnt-14, which is expressed early in the presumptive joint region, induces morphological and molecular changes indicative of an early joint interzone, suggesting that Wnt-14 plays a pivotal role in the induction of the joint interzone.