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

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