Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries.
Genes Dev, 2010/9/15;24(18):2068-80.
Affiliations
PMID: 20844017DOI: 10.1101/gad.1963210
Impact factor: 12.89
Abstract
Mutations in the X-linked human EPHRIN-B1 gene result in cleft palate and other craniofacial anomalies as part of craniofrontonasal syndrome (CFNS), but the molecular and developmental mechanisms by which ephrin-B1 controls the underlying developmental processes are not clear. Here we demonstrate that ephrin-B1 plays an intrinsic role in palatal shelf outgrowth in the mouse by regulating cell proliferation in the anterior palatal shelf mesenchyme. In ephrin-B1 heterozygous mutants, X inactivation generates ephrin-B1-expressing and -nonexpressing cells that sort out, resulting in mosaic ephrin-B1 expression. We now show that this process leads to mosaic disruption of cell proliferation and post-transcriptional up-regulation of EphB receptor expression through relief of endocytosis and degradation. The alteration in proliferation rates resulting from ectopic Eph-ephrin expression boundaries correlates with the more severe dysmorphogenesis of ephrin-B1(+/-) heterozygotes that is a hallmark of CFNS. Finally, by integrating phosphoproteomic and transcriptomic approaches, we show that ephrin-B1 controls proliferation in the palate by regulating the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signal transduction pathway.
MeSH terms
Animals; Cell Differentiation; Cell Proliferation; Craniofacial Abnormalities; Ephrin-B1; Ephrins; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Morphogenesis; Mutation; Palate; Receptor, EphB3; Signal Transduction; Syndrome; Up-Regulation
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