Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries.
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.
Bush
Jeffrey O
JO
Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Soriano
Philippe
P
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism*; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009024:Morphogenesis; D009154:Mutation; D010159:Palate / Q000033:anatomy & histology / Q000196:embryology* / Q000378:metabolism; D036223:Receptor, EphB3 / Q000378:metabolism; D015398:Signal Transduction; D013577:Syndrome; D015854:Up-Regulation
D036387:Ephrin-B1; D036342:Ephrins; D036223:Receptor, EphB3; D020929:Mitogen-Activated Protein Kinase Kinases