Ephrin‐B signaling in craniofacial development and disease

Mutations in the EPHRIN‐B1 gene result in X‐linked craniofrontonasal syndrome (CFNS), a condition that affects craniofacial, neurological, and skeletal development. Interestingly, although ephrin‐B1 is X‐linked, EPHRIN‐B1 +/− heterozygous females are more severely affected than hemizygous males. Ephrin‐B1 is a transmembrane protein that possesses bidirectional signaling capacity: it can engage Eph receptor tyrosine kinases to activate forward signaling, or can act as a receptor and signal into the cell in which it is expressed. By generating mice harboring targeted mutations disrupting specific signaling functions of ephrin‐B1, we have previously shown that reverse signaling is critical for a subset of ephrin‐B1 roles, but that forward signaling is required for craniofacial development. Here we explore the mechanisms by which ephrin‐B1 controls formation of the secondary palate. Ephrin‐B1 mutant mice display a cleft palate phenotype as a consequence of defective outgrowth of the anterior palatal shelves. By integrating phospho‐proteomic and microarray approaches we have explored the downstream signaling mechanisms responsible for ephrin‐B1 signal transduction in palatogenesis. Unexpectedly, ephrin‐B1 forward signaling utilizes ERK/MAPK signaling to regulate cell proliferation activity in the palatal mesenchyme. Whereas ephrin‐B1 +/− and ephrin‐B1 y/− mutant mice both display a cleft palate phenotype, ephrin‐B1 +/− heterozygous mice display more severe dysmorphogenesis of the palatal shelves than ephrin‐B1 y/− , a situation that parallels human CFNS. We propose a mechanism by which disrupted growth factor signaling by ephrin‐B1 may contribute to this mysterious aspect of CFNS. Grant Funding Source : NIH/NIDCR (1K99 DE020855 ‐ 01) to J.O.B.