# Growth Factor Signaling and Craniofacial Development

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $607,291

## Abstract

The major aims of this proposal are to identify signaling mechanisms underlying midface development that are
controlled by PDGF and FGF. Loss of the Pdgfra or Fgfr1 receptors leads to facial clefting and improper
development of the frontonasal process, whereas hypomorphic mutations in these pathways result in cleft palate.
Pdgfra and Fgfr1 regulate craniofacial development mainly in cranial neural crest cells (cNCCs) through PI3K
and Erk, respectively. PDGF induces a short duration or Erk signaling cell differentiation, whereas FGF promotes
cell proliferation and perdurance of the Erk signal. Last, PDGF and FGF regulate craniofacial development by
engaging immediate early genes (IEGs) through serum response factor (Srf), a critical transcription factor
activated by these growth factors itself required for midface closure. This application proposes:
1. To establish the roles and locations of PI3K and Erk signaling in craniofacial development. We will analyze
midface development in conditional PI3K and Erk core component genes in NCCs. To identify sites of PDGF
and FGF driven signaling activity in vivo, we will breed PI3K and Erk biosensors into wild type, Pdgfr and Fgfr
mutant backgrounds.
2. To determine how PDGF and FGF signaling differences differentially regulate craniofacial development. We
will alter the duration of Erk signaling in primary MEPMs using Mek/Erk and PKC inhibitors, and investigate how
this affects cell differentiation and proliferation. To establish the relative importance of combinatorial vs. dynamic
signaling and downstream responses in craniofacial development, we will analyze expression of known PDGF
and FGF transcriptional targets that are PI3K and Erk dependent and linked to differentiation or proliferative
responses, in Pdgfr/PI3K or Fgfr/Erk neural crest specific mutants.
3. To determine the signaling mechanisms through which Srf, a shared PDGF and FGF transcriptional target,
regulates differential transcriptional outputs. Srf interacts with two classes of co-factors, Myocardin Related
Transcription Factors (MRTFs) or Ternary Complex Factors (TCFs). PDGF promotes the association of Srf with
MRTFs through PI3K to regulate the expression of cytoskeletal target genes critical for craniofacial development,
whereas both PDGF and FGF allow Srf to interact with TCFs through PI3K and Erk signaling to facilitate the
expression of core IEGs. To establish the molecular pathways and targets by which growth factors regulate
midface development through Srf, we will generate mice carrying mutations in Srf that abrogate its ability to
associate with MRTFs, while maintaining its interactions with TCFs.
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:** 10226072
- **Project number:** 5R01DE022363-09
- **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:** 2021
- **Award amount:** $607,291
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226072

## Citation

> US National Institutes of Health, RePORTER application 10226072, Growth Factor Signaling and Craniofacial Development (5R01DE022363-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226072. Licensed CC0.

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