# FGF Signaling Pathways and Craniofacial Development

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $665,787

## Abstract

The major aims of this proposal are to identify signaling mechanisms initiated by FGFs that underlie craniofacial
morphogenesis. Loss of the FGFR1 receptor together with FGFR2 in neural crest cells leads to agenesis of
multiple components of the midface and mandible, whereas hypomorphic mutations in Fgfr1/2 result in cleft
palate. Elsewhere, FGFR2 rather than FGFR1 has a predominant role in salivary gland epithelia, and its activity
is differentially regulated by various ligands. Engagement of the FGF signaling cascade leads to dimerization of
the FGFRs, binding of multiple intracellular effectors and activation of cellular responses that converge on
ERK1/2 and several other pathways. This application proposes:
1. To investigate how FGF signaling coordinates midface development. Combined loss of both Fgfr1 and Fgfr2
in neural crest cells leads to facial clefting that extends through the midline, agenesis of the midface, mandibular
hypoplasia, and significant cell death in the lateral nasal and maxillary processes. To determine the origin of
these midface defects, Fgfr1/2 mandibular and/or lateral nasal /maxillary process conditional mutants will be
generated to investigate how loss of Fgfr1/2 in the mandible or lateral structures contributes to facial clefting.
Furthermore, neural crest Fgfr1/2 mutants will be crossed to Bim mutants to disassociate alterations in patterning
from BCL-2 family regulated cell death.
2. To identify signaling mechanisms promoted by Fgfr1 and Fgfr2 in craniofacial development. To identify
signaling pathways that remain active in a previously generated Fgfr1 and Fgfr2 allelic series of point mutations
that prevent the binding of single or multiple effector proteins and the initiation of specific signaling pathways, a
proteomic screen will be performed in mouse embryonic palatal mesenchyme cells using endogenous epitope
tagged FGFR1 and FGFR2 receptors. In a complementary approach, mice in which additional candidate tyrosine
phosphorylation sites are disrupted on the receptors will be generated.
3. To characterize signaling pathways specified by ligand identity. An emerging theme in FGF signaling is that
cellular responses in multiple physiological contexts can be encoded in the identity of the ligand and are not only
specified at the level of the receptor. Signaling responses that are differentially encoded by FGF7 and FGF10 in
submandibular salivary gland branching morphogenesis will be investigated. Critical downstream FGF pathways
in this response will be further identified by transcriptional profiling following stimulation with each ligand, and
morphogenetic responses that are sensitive to ERK1/2 and PI3K signaling and feedback inhibition pathways will
be investigated.
These proposed studies explore novel territories in the area of growth factor signaling in craniofacial biology and
open new directions for the prevention of craniofacial birth defects.

## Key facts

- **NIH application ID:** 10383149
- **Project number:** 5R01DE022778-10
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Philippe M Soriano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $665,787
- **Award type:** 5
- **Project period:** 2012-07-11 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383149

## Citation

> US National Institutes of Health, RePORTER application 10383149, FGF Signaling Pathways and Craniofacial Development (5R01DE022778-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10383149. Licensed CC0.

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