title: Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development.
abstract: 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 (Cdc42(fl/fl); Prx1-Cre) mice. Cdc42(fl/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 Cdc42(fl/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.
authors.affiliation: Department of Biochemistry, School of Dentistry, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Aizawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.forename: Dai
authors.initials: D
authors.lastname: Suzuki
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Iimura
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kassai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsukasaki
authors.forename: Gou
authors.initials: G
authors.lastname: Yamamoto
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Tachikawa
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.forename: Matsuo
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Kamijo
mesh_terms: D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation; D020219:Chondrogenesis; D005260:Female; D005528:Foot / Q000196:embryology*; D005532:Foot Deformities, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006132:Growth Plate / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D018878:Limb Buds / Q000166:cytology / Q000196:embryology; D051957:MSX1 Transcription Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C581598:Cdc42 protein, mouse; D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse; D020764:cdc42 GTP-Binding Protein