Receptor tyrosine kinases modulate distinct transcriptional programs by differential usage of intracellular pathways

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Abstract

Receptor tyrosine kinases (RTKs) signal through shared intracellular pathways yet mediate distinct outcomes across many cell types. To investigate the mechanisms underlying RTK specificity in craniofacial development, we performed RNA-seq to delineate the transcriptional response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells. While the early gene expression profile induced by both growth factors is qualitatively similar, the late response is divergent. Comparing the effect of MEK (Mitogen/Extracellular signal-regulated kinase) and PI3K (phosphoinositide-3-kinase) inhibition, we find the FGF response is MEK-dependent while the PDGF response is PI3K-dependent. Further, FGF promotes proliferation but PDGF favors differentiation. Finally, we demonstrate overlapping domains of PDGF-PI3K signaling and osteoblast differentiation in the palate and increased osteogenesis in FGF mutants, indicating this differentiation circuit is conserved in vivo. Our results identify distinct responses to PDGF and FGF and provide insight into the mechanisms encoding RTK specificity.

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Harish N Vasudevan

Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Pierre Mazot

Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Fenglei He

Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Philippe Soriano

Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States

For correspondence
philippe.soriano@mssm.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#11-00243) of Icahn School of Medicine at Mt. Sinai.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.