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

• DOI: 10.1101/704619
• Publication Date: 2019-07-16T16:55:10Z
• Authors: Terren K. Niethamer; Christopher J. Pe...; Teng Teng; Melanie Franco; Yu Xin Du; Jeffrey O. Bush
• Keywords: Craniofacial abnormality; Loss function

Abstract 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 male patients, phenomenon called cellular interference that correlated with cell segregation resulting from EPHRIN-B1 mosaicism. Efnb1 heterozygous mutant mice also exhibit severe phenotypes males as well segregation, but how craniofacial dysmorphology arises unknown etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques temporal spatial interrogation of embryonic mouse models to elucidate mechanisms underlying pathogenesis. By generating ephrin-B1 mosaicism 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 throughout does not appear contribute dysmorphology, its within crest cell-derived mesenchyme results very widespread loss. Ephrin-B1 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 recapitulate CFNS-like severity. Finally, +/- ; quadruple knockout mice, determine modulating cumulative activity influences while play important role EphB1 for brain; surprisingly, EphB1-EphB3 completely abrogate segregation. Together, these data advance our understanding morphogenetic interactions dysmorphology. Author Summary Craniofacial extremely common, accounting one third all birth defects, even when responsible genes known, it often be determined exactly has gone wrong. (CFNS), which affects multiple aspects particularly mysterious because X-linked, males, opposite situation most diseases. The gene been identified , encodes molecule position. Why stereotypical understood, related fact X chromosome inactivation generates EPHRIN-B1. Using harboring tissues, Ephb1-3 together methods measure structures developing establish contributions We examine position during stages EphB involved. Our reveal context likely underlie CFNS, provide new may regulate normal development.