Rho family small G proteins: Lessons from tissue-specific gene knockout studies

Rac1 and Cdc42 are Rho small GTPases known to regulate multiple cellular functions including cytoskeletal organization, proliferation, and apoptosis. Recently, their tissue-specific roles have been uncovered, particularly in mammalian limb development, using limb bud mesenchyme-specific inactivated Rac1 (Rac1fl/fl; Prx1-Cre; and Rac1 cKO) and Cdc42 (Cdc421fl/fl; Prx1-Cre; and Cdc42 cKO) conditional knockout (cKO) mice. Both strains demonstrated striking syndactyly of the fore- and hindlimbs. In Rac1 cKO mice, this condition is caused by a failure of interdigital programmed cell death (ID-PCD) while, in Cdc42 cKO mice, a failure of ID-PCD and fusion of metacarpals caused syndactyly. Expression of BMPs and their target signaling molecules, known to have critical roles in limb development including skeletal formation and ID-PCD, is reduced in both strains. These results indicate that Rac1 and Cdc42 regulate BMP signaling during limb development. In this review, the recent findings regarding the mesenchymal functions of Rac1 and Cdc42 during limb development are summarized.