Zhang Beibei, Pan Xiaoyun, Chi Dandan, Wang Yumeng, Ruan Wenyan, Ma Jian, Duan Xiaohong, Huang Yongqing
Ningxia Key Laboratory of Oral Disease Research, Ningxia Key Laboratory of Craniomaxillofacial Deformities Research, School of Stomatology, Ningxia Medical University, Yinchuan 750004, China.
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
Int J Mol Sci. 2025 May 13;26(10):4647. doi: 10.3390/ijms26104647.
The gene encodes Rho-GTPase-activating protein 29 (), which plays a crucial role in embryonic tissue development. Mutations in the gene are significantly associated with non-syndromic cleft lip and palate (NSCL/P). Our study demonstrated that the deletion of leads to syndromic cleft lip and palate (SCL/P) characteristics in mice, where, in addition to cleft palate, the mice exhibit craniofacial and systemic skeletal abnormalities. However, the mechanisms underlying these skeletal abnormalities remain unclear. Through micro-CT imaging, histological analysis, and transcriptomic methods, we discovered that the knockout of delays the fusion of Meckel's cartilage, widens cranial sutures, reduces bone quality, and alters the expression of osteoblasts and osteoclasts in the mandible. Digit defects, including ectrodactyly and impaired endochondral ossification, were also observed. Immunohistochemical analysis demonstrated the expression of in both osteoblasts and osteoclasts, indicating its dual role in maintaining matrix homeostasis and regulating bone resorption equilibrium. Transcriptomic analysis revealed disrupted calcium and MAPK signaling pathways, while in vitro studies demonstrated impaired osteogenesis in -deficient calvarial cells, mirroring the in vivo defects. Furthermore, spatial transcriptomics linked the loss of to defective bone differentiation and protein synthesis. Our findings underscore the critical role of in the development of the mandible and digits, suggesting its potential as a pathogenic gene associated with syndromic cleft lip and palate (SCL/P).
该基因编码Rho-GTPase激活蛋白29（），其在胚胎组织发育中起关键作用。该基因的突变与非综合征性唇腭裂（NSCL/P）显著相关。我们的研究表明，该基因的缺失会导致小鼠出现综合征性唇腭裂（SCL/P）特征，除腭裂外，小鼠还表现出颅面和全身骨骼异常。然而，这些骨骼异常背后的机制仍不清楚。通过微CT成像、组织学分析和转录组学方法，我们发现该基因的敲除会延迟梅克尔软骨的融合，加宽颅缝，降低骨质量，并改变下颌骨中破骨细胞和成骨细胞的表达。还观察到包括并指畸形和软骨内成骨受损在内的指骨缺陷。免疫组织化学分析表明该蛋白在成骨细胞和破骨细胞中均有表达，表明其在维持基质稳态和调节骨吸收平衡方面具有双重作用。转录组分析揭示了钙和丝裂原活化蛋白激酶（MAPK）信号通路的紊乱，而体外研究表明该基因缺陷的颅骨细胞成骨受损，这与体内缺陷情况相符。此外，空间转录组学将该基因的缺失与有缺陷的骨分化和蛋白质合成联系起来。我们的研究结果强调了该基因在下颌骨和指骨发育中的关键作用，表明其作为与综合征性唇腭裂（SCL/P）相关的致病基因的潜力。
