Unraveling the Cellular Dynamics of the Cranial Base Synchondroses Throughout Postnatal Craniofacial Development

颅底生长中心软骨综合征对出生后颅面双向调节是必不可少的 形成上鼻道的结构基础，形成面中部的生长和骨骼图样 咀嚼情结。与长骨生长板相似，软骨中的软骨细胞是有组织的。 变成在骨骼成熟时骨化的静息区、增殖区和肥大区。重要的是，组织 而增殖的软骨细胞的激活是促进颅底生长所必需的。成纤维细胞生长因子 FGFR3受体在软骨细胞中表达，FGFR3功能获得突变引起 与软骨发育不全相关的合并症和面中部发育不全 老鼠。目前面中部发育不全的治疗仅限于颅面和正颌重建。 给病人做手术。尽管有这些有临床意义的发现，但FGFR3软骨细胞的行为尚不清楚 在整个出生后的联合软骨生长过程中。因此，这项提案的总体目标是确定机制 通过FGFR3增殖的软骨细胞协调出生后软骨的生长和成熟。我的 初步数据表明，与侏儒相关的锁骨颅骨发育不良的致病基因的条件性缺失 小鼠FGFR3软骨细胞中的转录因子2(Runx2)会导致软骨过早融合， 软骨细胞肥大加速，成骨细胞形成减少。虽然《Runx2》的S扮演了核心角色 长骨中已经建立了成骨细胞分化和骨形成的调节因子，其功能在 合并症的发展仍不清楚。结合我们目前对FGFR3相关颅脑的知识 碱基畸形根据我大量的初步数据，我假设表达FGFR3的软骨细胞 保持出生后颅底软骨的双向定向和生长潜力 通过一种依赖于Runx2激活的机制。 针对这一中心假设，本文提出了两个目标。1.评价克隆动力学和细胞 FGFR3软骨细胞在关节软骨中的异质性。2.明确Runx2在FGFR3软骨细胞中的作用 同步软骨中的组织。这个项目试图提供对出生后的新的机械洞察力。 同步软骨的生长和成熟，从而推动了当前颅底生物学的科学状态。 此外，这些调查旨在揭开一种将Runx2作为中央调节器的创新机制 出生后合并症的发展。值得注意的是，该项目打算催化未来的研究 具有治疗靶向性的FGFR3相关通路在畸形软骨患者中发生突变。

The cranial base growth center synchondroses are essential for regulating bidirectional postnatal craniofacial growth and skeletal patterning of the midface by forming the structural foundation for the upper nasal airway and masticatory complex. Similar to the long bone growth plate, chondrocytes in the synchondroses are organized into resting, proliferating and hypertrophic zones that ossify during skeletal maturation. Importantly, organization and activation of proliferating chondrocytes is required to promote cranial base growth. Fibroblast growth factor receptor 3 (Fgfr3) is expressed in chondrocytes in the synchondroses and Fgfr3 gain-of-function mutations cause achondroplasia associated with premature fusion of the synchondroses and midfacial hypoplasia in humans and mice. Current treatments for midfacial hypoplasia are limited to craniofacial and orthognathic reconstructive surgeries in patients. Despite these clinically meaningful findings, it is unknown how Fgfr3+ chondrocytes behave throughout postnatal synchondrosis growth. Therefore, the overall goal of this proposal is to identify mechanisms by which Fgfr3+ proliferating chondrocytes orchestrate postnatal synchondrosis growth and maturation. My preliminary data suggests that conditional deletion of the causative gene for cleidocranial dysplasia, runt-related transcription factor 2 (Runx2), in Fgfr3+ chondrocytes in mice causes premature fusion of the synchondroses, accelerated chondrocyte hypertrophy and decreased osteoblast formation. Although Runx2’s role as a central regulator of osteoblast differentiation and skeletal formation has been established in long bones, its function in synchondrosis development remains unknown. By combining our current knowledge of Fgfr3-related cranial base malformations with my extensive preliminary data, I hypothesize that Fgfr3-expressing chondrocytes maintain the bidirectional orientation and growth potential of the postnatal cranial base synchondroses through a mechanism dependent on Runx2 activation. Two aims are proposed to address the central hypothesis. 1. Assess the clonal dynamics and cellular heterogeneity of Fgfr3+ chondrocytes in the synchondroses. 2. Define the role of Runx2 on Fgfr3+ chondrocyte organization in the synchondroses. This project seeks to provide novel mechanistic insight into postnatal synchondrosis growth and maturation, thereby advancing the current scientific state of cranial base biology. Furthermore, these investigations aim to unravel an innovative mechanism placing Runx2 as a central regulator of postnatal synchondrosis development. Notably, this project intends to catalyze future studies into therapeutically targetable Fgfr3-related pathways mutated in patients with malformed synchondroses.