Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries.

Publication Type:

Journal Article

Source:

Genes & development, Volume 24, Issue 18, p.2068-80 (2010)

Keywords:

2010, Animals, Basic Sciences Division, Cell Differentiation, Cell Proliferation, Center-Authored Paper, Craniofacial Abnormalities, Ephrin-B1, EPHRINS, MICE, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases, MORPHOGENESIS, Mutation, Palate, Receptor, EphB3, Signal Transduction, Syndrome, Up-Regulation

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.