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. 2025 Aug;254(8):979-998.
doi: 10.1002/dvdy.70041. Epub 2025 May 20.

Downstream branches of receptor tyrosine kinase signaling act interdependently to shape the face

Nicholas Hanne  1 , Diane Hu  1 , Marta Vidal-García  2 , Charlie Allen  3 , M Bilal Shakir  2 , Wei Liu  2 , Benedikt Hallgrímsson  2 , Ralph Marcucio  1
Affiliations

Downstream branches of receptor tyrosine kinase signaling act interdependently to shape the face

Nicholas Hanne et al. Dev Dyn. 2025 Aug.

Abstract

Background: Previously we found that increasing fibroblast growth factor (FGF) signaling in the neural crest cells within the frontonasal process (FNP) of the chicken embryo caused dysmorphology that was correlated with reduced proliferation, disrupted cellular orientation, and lower MAPK activation but no change in PLCγ and PI3K activation. This suggests RTK signaling may drive craniofacial morphogenesis through specific downstream effectors that affect cellular activities. In this study we inhibited three downstream branches of RTK signaling to determine their role in regulating cellular activities and how these changes affect morphogenesis of the FNP.

Results: Small molecule inhibitors of MEK1/2, PI3K, and PLCγ were delivered individually and in tandem to the right FNP of chicken embryos. All treatments caused asymmetric proximodistal truncation on the treated side and a mild expansion on the untreated side compared to DMSO control treated FNPs. Inhibiting each pathway caused similar decreased proliferation and disrupted cellular orientation, and only mildly increased apoptosis.

Conclusions: Since RTK signaling is a ubiquitous and tightly regulated biochemical system, we conclude that the downstream pathways are robust to developmental perturbation through redundant signaling systems.

Keywords: cellular activity; craniofacial; morphogenesis; tyrosine kinase signaling.

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