# Coronal Suture Development in Health and Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $785,193

## Abstract

ABSTRACT
Skull development requires the proper function of sutures, comprised of the edges of adjacent bones (osteogenic
fronts, OFs) and intervening suture mesenchyme (SM). Suturogenesis is a complex and intriguing process,
particularly for the coronal suture between the frontal and parietal bones of the calvaria. Coronal suturogenesis
involves the migration of osteoprogenitors through ectocranial mesenchyme to the OFs at early embryonic
stages and maintenance of the SM to preserve an open suture that develops a stem cell niche postnatally.
Misregulation of suturogenesis is a significant source of human pathology, such as wider sutures or
craniosynostosis (CRS), the premature fusion of sutures. CRS can adversely affect neurological development
and requires corrective surgery. The coronal suture is the most frequently fused suture in syndromic CRS, which
is generally thought to result from an imbalance between osteoprogenitor induction, proliferation, and
differentiation. The cell populations involved are poorly defined in terms of their transcriptional signatures and
spatial organization, hindering understanding of the effects of genes mutated in coronal CRS. Understanding the
pathogenesis of CRS has positive implications for human health in providing insight toward treating dysgenesis.
In this proposal we will analyze murine coronal suturogenesis in three increasingly focused Aims: 1) define the
organization of transcriptionally-characterized cell populations; 2) establish the roles of a newly identified SM
population; and 3) investigate the role of the hedgehog (HH) signaling pathway that when altered can result in
CRS in humans and mice. For Aim 1, we will generate and integrate spatial transcriptomics and single-cell
(sc)RNA-seq analyses between embryonic day (E)12.5-E18.5 in wild type (WT) mice and two models of
syndromic coronal CRS. From this, we will generate a detailed 4D representation of the transcriptional signatures
and spatial organization of cell populations and identify potential mechanisms of dysgenesis in coronal CRS. For
Aim 2, by scRNA-seq analysis we have identified a discreet population within the SM that separates the
overlapping frontal and parietal bones of the coronal suture. We will use targeted genetic manipulations to ablate
and fate map this population, and perform lineage differentiation and calvarial defect assays. These experiments
will determine the function of this SM population as a barrier to prevent fusion of adjacent bones and their
potential contribution to suture stem cells. For Aim 3, we have identified a novel coronal suture phenotype in
mutants of Hhip, a HH inhibitor highly expressed in the SM population studied in Aim 2. We will characterize the
Hhip-/- phenotype and combine targeted genetic manipulations of the HH pathway in the SM population with
RNA-seq analysis to comprehensively determine the roles of HH signaling at the level of both transcriptional
programs and cell populations. We will fate m...

## Key facts

- **NIH application ID:** 10491859
- **Project number:** 5R01DE030596-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Greg Peter Holmes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $785,193
- **Award type:** 5
- **Project period:** 2021-09-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491859

## Citation

> US National Institutes of Health, RePORTER application 10491859, Coronal Suture Development in Health and Disease (5R01DE030596-02). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10491859. Licensed CC0.

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