# Fgf signaling in patterning of the calvarial joints

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $460,174

## Abstract

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.

## Key facts

- **NIH application ID:** 10878687
- **Project number:** 5R01DE025222-07
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Amy E Merrill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,174
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878687

## Citation

> US National Institutes of Health, RePORTER application 10878687, Fgf signaling in patterning of the calvarial joints (5R01DE025222-07). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10878687. Licensed CC0.

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