THE ROLE OF CYCLIN-DEPENDENT KINASE-5 AND A NOVEL REGULATORY SUBUNIT IN REGULATING MUSCLE DIFFERENTIATION AND PATTERNING

Cyclin-dependent kinase 5, coupled with its activator p35, is required for normal neuronal differentiation and patterning. We have isolated a novel member of the p35 family, Xp35.1, from Xenopus embryos which c an activate cdk5. Xp35.1 is expressed in both proliferating and differ entiated neural and mesodermal cells and is particularly high in devel oping somites where cdk5 is also expressed. Using dominant-negative cd k5 (cdk5 DN), we show that cdk5 kinase activity is required for normal semitic muscle development; expression of cdk5 DN results in disrupti on of semitic muscle patterning, accompanied by stunting of the embryo s. Using explants of animal pole tissue from blastula embryos, which w ill differentiate into mesoderm in response to activin, we show that b locking cdk5 kinase activity down-regulates the expression of the musc le marker muscle actin in response to activin, whereas the pan-mesoder mal marker Xbra is unaffected. Expression of MyoD and MRF4 (master reg ulators of myogenesis) is suppressed in the presence of cdk5 DN, indic ating that these myogenic genes may be a target for cdk5 regulation, w hereas the related factor Myf5 is largely unaffected. In addition, ove rexpression of Xp35.1 disrupts muscle organization. Thus, we have demo nstrated a novel role for cdk5 in regulating myogenesis in the early e mbryo. The sequence data described in this paper have been submitted t o GenBank under accession no. AF000951.].