Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development

• Published in: Mechanisms of development Vol. 129; no. 1-4; pp. 38 - 50
• Main Authors: Aizawa, Ryo, Yamada, Atsushi, Suzuki, Dai, Iimura, Tadahiro, Kassai, Hidetoshi, Harada, Takeshi, Tsukasaki, Masayuki, Yamamoto, Gou, Tachikawa, Tetsuhiko, Nakao, Kazuki, Yamamoto, Matsuo, Yamaguchi, Akira, Aiba, Atsu, Kamijo, Ryutaro
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.03.2012
• Subjects: Animals; Apoptosis; Body Patterning; Bone Morphogenetic Protein 2 - metabolism; Cdc42; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell Differentiation; Chondrogenesis; Conditional knockout mice; Female; Foot - embryology; Foot Deformities, Congenital - genetics; Foot Deformities, Congenital - metabolism; Foot Deformities, Congenital - pathology; Gene Expression; Growth Plate - abnormalities; Growth Plate - embryology; Growth Plate - metabolism; Limb Buds - cytology; Limb Buds - embryology; Limb development; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; MSX1 Transcription Factor - metabolism; Programmed cell death; Programmed cell death; Conditional knockout mice; Chondrogenesis; Cdc42; Limb development
• ISSN: 0925-4773; 1872-6356
• DOI: 10.1016/j.mod.2012.02.002

► Limb bud mesenchyme-specific inactivated Cdc42 conditional knockout mice, Cdc42 cKO. ► Severe skeletal defects in Cdc42 cKO during limb development. ► Reduction of interdigital programmed cell death in Cdc42 cKO. Cdc42, a member of the Rho subfamily of small GTPases, is known to be a regulator of multiple cellular functions, including cytoskeletal organization, cell migration, proliferation, and apoptosis. However, its tissue-specific roles, especially in mammalian limb development, remain unclear. To investigate the physiological function of Cdc42 during limb development, we generated limb bud mesenchyme-specific inactivated Cdc42 (Cdc42fl/fl; Prx1-Cre) mice. Cdc42fl/fl; Prx1-Cre mice demonstrated short limbs and body, abnormal calcification of the cranium, cleft palate, disruption of the xiphoid process, and syndactyly. Severe defects were also found in long bone growth plate cartilage, characterized by loss of columnar organization of chondrocytes, and thickening and massive accumulation of hypertrophic chondrocytes, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed that expressions of Col10 and Mmp13 were reduced in non-resorbed hypertrophic cartilage, indicating that deletion of Cdc42 inhibited their terminal differentiation. Syndactyly in Cdc42fl/fl; Prx1-Cre mice was caused by fusion of metacarpals and a failure of interdigital programmed cell death (ID-PCD). Whole mount in situ hybridization analysis of limb buds showed that the expression patterns of Sox9 were ectopic, while those of Bmp2, Msx1, and Msx2, known to promote apoptosis in the interdigital mesenchyme, were down-regulated. These results demonstrate that Cdc42 is essential for chondrogenesis and ID-PCD during limb development.