# Genomic control of neural crest identity by signaling systems

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $357,928

## Abstract

PROJECT SUMMARY / ABSTRACT
The neural crest is an embryonic stem cell population that gives rise to multiple derivatives, including most of
the craniofacial skeleton. The formation of neural crest cells is controlled by a gene regulatory network (GRN)
that endows these progenitor cells with their unique features, including multipotency and the ability to migrate.
This complex molecular program is modulated by extracellular signals that ensure precise spatial control of
neural crest specification. In particular, the Wingless (Wnt) signaling pathway has been shown to play a pivotal
role in the establishment of craniofacial cell types. Despite the importance of this signaling pathway, only a few
direct Wnt targets have been identified within the neural crest GRN. Furthermore, we also lack a mechanistic
understanding of how Wnts cooperate with other signaling systems, such as the Bone Morphogenetic Protein
(BMP) pathway, during early neural crest development. To identify novel targets of canonical Wnt signaling, we
surveyed the genomic occupancy of Wnt nuclear effectors Lef1 and β-catenin in nascent avian neural crest
cells. This analysis uncovered multiple neural crest genes that are controlled via tissue-specific Wnt-
responsive enhancers. Intriguingly, we found that the genomic regions occupied by both Lef1/β-catenin also
contained multiple binding motifs for Smads, the nuclear effectors of BMP signaling. Accordingly, we
hypothesize that canonical Wnts cooperate with BMPs to initiate the neural crest gene GRN at the neural plate
border. We will test this hypothesis by (a) identifying the direct Wnt target genes in the neural crest GRN; (b)
defining how combinatorial input of Wnt and BMP signaling systems affects the output of the neural crest
enhancers; and (c) determining how effectors of Wnts and BMPs interact to control gene expression. The
overarching goal of this proposal is to define how environmental cues impact gene expression in a genome-
wide manner to modulate cell identity. We anticipate that the findings of this proposal will provide a
comprehensive model of how enhancers integrate inputs from distinct signaling systems to activate complex
transcriptional programs. The mechanisms uncovered in this work will impact not only tissue engineering but
also inform upon abnormal shifts in cell identity that are relevant to human health, such as cancer and
congenital malformations.

## Key facts

- **NIH application ID:** 10165694
- **Project number:** 5R01DE028576-03
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Marcos Simoes-Costa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,928
- **Award type:** 5
- **Project period:** 2019-09-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165694

## Citation

> US National Institutes of Health, RePORTER application 10165694, Genomic control of neural crest identity by signaling systems (5R01DE028576-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165694. Licensed CC0.

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