# Substrate-mediated collective cell migration incalvarial bone expansion and disease.

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $682,663

## 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, and thus etiology of these
disorders. The Harris and Atit laboratories have 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 cranial 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 diverse mouse
models of craniosynostosis to assess commonality of fibronectin disruption in clinically relevant dysmorphologies
and whether decreasing fibronectin expression rescues craniosynostosis in 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 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:** 10801205
- **Project number:** 1R01DE032670-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** RADHIKA P ATIT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $682,663
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801205

## Citation

> US National Institutes of Health, RePORTER application 10801205, Substrate-mediated collective cell migration incalvarial bone expansion and disease. (1R01DE032670-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801205. Licensed CC0.

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