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

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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.