Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The calvarial bones of the infant skull are separated by fibrous connective tissue joints called sutures and fontanelles. These joints are critical for early reshaping of the skull during birth and brain growth. Improper fusion of these joints, both premature and delayed, results in craniofacial deformities seen in numerous genetic disorders. In this proposal, we aim to study the relatively uncharacterized role of calvarial connective tissue (CT) to better understand its role in calvarial joint development and pathology. We hypothesize that lineage-dependent, regional signaling from CT orchestrates distinct differences in morphology, mechanism of fusion, and susceptibility to abnormal closure among calvarial joints. Using both cutting-edge multiomics technology and mouse genetics, we will resolve differences across calvarial joint CTs in both normal and disease contexts. Syndromes featuring premature suture fusion (craniosynostosis) and delayed fontanelle closure are commonly associated with variants in Fibroblast growth factor receptor 2 (FGFR2). Although most research thus far has focused exclusively on the role of Fgfr2 in the bone, our lab has revealed its importance in developing joint CT, including tendon and ligament. We will, therefore, apply these findings to study the role of Fgfr2 in calvarial CT using both loss- and gain-of-function alleles in mice. Our preliminary data shows that Fgfr2 loss-of-function in the neural crest cells (NCC) blocks normal contribution of CT fibroblasts to the advancing bone fronts in the anterior fontanelle (AF) resulting in its patency. Conversely, our gain-of-function model featuring the Fgfr2M391R variant in Bent bone dysplasia syndrome (BBDS) shows that activation in the NCC leads to multi-suture synostosis, most interestingly in sutures where only CT (and not bone) is NCC- derived. Conversely, Fgfr2M391R activation in mesoderm does not affect suture patency. The NCC-specific nature of these phenotypes suggests regional, lineage-dependent regulation of CT. In this proposal, we aim to identify and characterize gene expression and regulatory networks within CT fibroblast subtypes, as well as their spatial arrangements and fate trajectories, in different sutures and fontanelles. We predict that regional regulation of Wnt, Fgf, and retinoic acid signaling pathways play a key role in the organization and fusion of normal sutures by affecting cell fate potential. Additionally, we will explore the novel concept that non- canonical, nuclear signaling of Fgfr2 orchestrates these processes via differential gene regulation in calvarial CT fibroblasts. This study is expected to show that CT fibroblasts are signaling centers that direct calvarial joint development and underlie region-specific fusion patterns in congenital skull deformities.
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