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Development. 2014 Jul;141(13):2611-20. doi: 10.1242/dev.107078. Epub 2014 Jun 12.

Nuclear to cytoplasmic shuttling of ERK promotes differentiation of muscle stem/progenitor cells.

Author information

1
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Theoretical Systems Biology, Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK.
3
Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA 94143-0430, USA.
4
Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA 94143-0430, USA Department of Pediatrics, Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143-0442, USA.
5
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel eldad.tzahor@weizmann.ac.il.

Abstract

The transition between the proliferation and differentiation of progenitor cells is a key step in organogenesis, and alterations in this process can lead to developmental disorders. The extracellular signal-regulated kinase 1/2 (ERK) signaling pathway is one of the most intensively studied signaling mechanisms that regulates both proliferation and differentiation. How a single molecule (e.g. ERK) can regulate two opposing cellular outcomes is still a mystery. Using both chick and mouse models, we shed light on the mechanism responsible for the switch from proliferation to differentiation of head muscle progenitors and implicate ERK subcellular localization. Manipulation of the fibroblast growth factor (FGF)-ERK signaling pathway in chick embryos in vitro and in vivo demonstrated that blockage of this pathway accelerated myogenic differentiation, whereas its activation diminished it. We next examined whether the spatial subcellular localization of ERK could act as a switch between proliferation (nuclear ERK) and differentiation (cytoplasmic ERK) of muscle progenitors. A myristoylated peptide that blocks importin 7-mediated ERK nuclear translocation induced robust myogenic differentiation of muscle progenitor/stem cells in both head and trunk. In the mouse, analysis of Sprouty mutant embryos revealed that increased ERK signaling suppressed both head and trunk myogenesis. Our findings, corroborated by mathematical modeling, suggest that ERK shuttling between the nucleus and the cytoplasm provides a switch-like transition between proliferation and differentiation of muscle progenitors.

KEYWORDS:

Chick; ERK; FGF signaling; Mouse; Myogenesis

PMID:
24924195
PMCID:
PMC4067960
DOI:
10.1242/dev.107078
[Indexed for MEDLINE]
Free PMC Article

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