Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

• DOI: 10.1371/journal.pgen.1008300
• Publication Date: 2020-02-24T18:45:58Z
• Authors: Terren K. Niethamer; Teng Teng; Melanie Franco; Yu Xin Du; Christopher J. Pe...; Jeffrey O. Bush
• Keywords: Craniofacial abnormality; Ephrin; Loss function

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies caused mutations in EFNB1. Heterozygous females are more severely affected CFNS than hemizygous males, phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for cell sorting severe phenotypes but how craniofacial dysmorphology arises segregation unknown etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal spatial interrogation of embryonic mouse mutant models to elucidate mechanisms underlying pathogenesis. By generating at different developmental timepoints specific populations, find regulates independently early neural development later development, correlating the emergence quantitative differences face shape. Whereas shape changes qualitatively similar embryos, embryos quantitatively affected, indicating exacerbates loss function rather having neomorphic effect. Notably, tissue-specific disruption does not appear contribute dysmorphology, its within crest cell-derived mesenchyme very widespread loss. can bind signal EPHB1, EPHB2, EPHB3 receptor tyrosine kinases, signaling partner(s) relevant unknown. Geometric analysis an allelic series Ephb1; Ephb2; Ephb3 indicates EPHB2 key receptors mediating hemizygous-like phenotypes, complete EPHB1-3 fully recapitulate severity CFNS-like heterozygosity. Finally, Efnb1+/Δ; quadruple knockout determine modulating cumulative activity influences while play important role segregation, EPHB1 brain; surprisingly, EPHB1-EPHB3 completely abrogate segregation. Together, these data advance our understanding interactions dysmorphology.