# Mechanisms of apical expansion in calvarial bone morphogenesis

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $172,855

## Abstract

Congenital skull defects such as craniosynostosis and dysplasias occur in 1/2500 live
births with detrimental consequences for brain and sensory organ development. We lack basic
understanding of how and why the skull bones grow towards the apex, which impacts the direction
of intramembranous mineralization and fusion of sutures. The signaling factors and cellular
mechanisms underlying the apical expansion of skull bone progenitors remain unidentified.
 We recently found mouse skull bone progenitors migrate from the supraorbital arch region
to the apex and this movement is disrupted in conditional mesenchyme Wntless mutants, that
lack all ligand secretion. We also identified a graded expression of fibronectin extracellular matrix
in the cranial mesenchyme that is dependent on mesenchyme Wnts, suggesting cell movement
by a process of durotaxis in which cells migrate along a stiffness gradient of fibronectin. This
proposal intends to define, in vivo, the role of the cranial mesenchyme non-canonical Wnts in
directing cellular polarity and durotaxis. In this multi-PI proposal, we will leverage our integrative
expertise in conditional mouse genetics, live cell imaging, and emerging biophysical approaches
in vivo to address our central hypothesis that mesenchyme Wnts-dependent fibronectin
orients the collective movement of calvarial bone progenitors toward the apex by
durotaxis. Towards the hypothesis, in Aim1 we will identify the role of mesenchyme Wnts
signaling in regulating cell movement behaviors with live light-sheet imaging. In Aim2, we will test
if fibronectin directs a tissue-stiffness gradient and collective movement of SOM cells apically by
durotaxis. Key deliverables of this R21 proposal include: 1. Developing a framework of cellular
behaviors during calvarial bone morphogenesis, 2. the role of SOM-Wnt as a global spatial cue,
and 3. the role of durotaxis driven cell movements on a graded fibronectin matrix during calvarial
bone growth.
Impact: Currently, we lack a conceptual framework for understanding cell movement in calvarial
bone expansion, despite its role in highly prevalent craniosynostosis and cranial skeletal
dysplasias. The results from these proof-of-concept experiments will serve as a new paradigm
in our understanding of cell movement in 3D in mesenchymal cells and provide us fresh insights
into skull bone morphogenesis and congenital defects.

## Key facts

- **NIH application ID:** 10212367
- **Project number:** 5R21DE029348-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** RADHIKA P ATIT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $172,855
- **Award type:** 5
- **Project period:** 2020-07-07 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212367

## Citation

> US National Institutes of Health, RePORTER application 10212367, Mechanisms of apical expansion in calvarial bone morphogenesis (5R21DE029348-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212367. Licensed CC0.

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