# Substrate-mediated collective cell migration in calvarial bone expansion and disease

> **NIH NIH R56** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $570,819

## Abstract

Summary
Congenital defects affecting the formation of the skull roof, such as craniosynostosis or persistent fontanelles,
occur as a result of abnormal calvarial growth and differentiation. We lack a basic understanding of how calvarial
bones grow, which in turn impacts the position, patterning, and fusion of sutures. The Harris and Atit laboratories
recently uncovered an unexpected and intriguing role for cellular sensing of graded fibronectin matrix in
preferentially regulating apical expansion of calvarial progenitors during mouse development. When cellular
lamellipodia are inhibited, mouse calvarial osteoblasts fail to appropriately migrate resembling defects seen when
we conditionally delete fibronectin. These findings are bolstered by data that fibronectin is misregulated in
patients with craniosynostosis as well as animal models of this disease. We propose that graded fibronectin may
act as a substrate for coordinated migration of calvarial osteoblast progenitors over the skull roof. Our central
hypothesis is that calvarial growth and suture patency are dependent on fibronectin-directed calvarial
progenitor cell expansion. Through three focused mechanistic and translational aims, we will directly test this
model and hypothesis of fibronectin substrate-mediated migration underlying a diverse number of suture
pathologies. First, we will assess outcomes of altered fibronectin expression in regulation of calvarial growth.
Second, using newly established genetic lines in mouse and zebrafish, we will test the dependence on fibronectin
adhesion and the role of lamellipodia-dependent cellular sensing of an extracellular gradient in apical expansion
of calvaria. Third, we will capitalize on both patient and mouse models of craniosynostosis to assess commonality
of fibronectin disruption in clinically relevant dysmorphologies and whether decreasing fibronectin expression
rescues craniosynostosis in zebrafish and mouse models in vivo. Our unique genetic tools in both mouse and
zebrafish will allow us to define the function of fibronectin guided lamellipodia-based collective cell movement in
vivo during calvarial bone expansion and the impact of fibronectin deficiency on suture patency. Results from
these studies will help detail the substrate-mediated cell migration of osteoblast progenitors and will lead to new
strategies for targeted therapies of calvarial bone defects and craniofacial disorders.

## Key facts

- **NIH application ID:** 10427074
- **Project number:** 1R56DE030206-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** RADHIKA P ATIT
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,819
- **Award type:** 1
- **Project period:** 2021-08-03 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427074

## Citation

> US National Institutes of Health, RePORTER application 10427074, Substrate-mediated collective cell migration in calvarial bone expansion and disease (1R56DE030206-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10427074. Licensed CC0.

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