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首页> 外文期刊>PLoS Genetics >Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome
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Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome

机译：在颅面原基中的异常细胞分离和颅孢菌综合征中面部缺血性的出现

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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.
机译：CraniofrontOnasal综合征（CFN）是一种罕见的X链接疾病，其特征在于颅面，骨骼和神经异常，并且是由EFNB1中的突变引起的。杂合的女性受CFNs的影响比嗜血性雄性更严重，一种称为细胞干扰的现象，由Ephrin-B1镶嵌产生。在EFNB1杂合小鼠中，用于ephrin-B1的镶嵌主义导致细胞分选和比EFNB1嗜血项的更严重的表型，但是如何从细胞分离产生的颅面缺血性如何未知，因此CFNS病因因此仍然不知情。在这里，我们对小鼠突变模型中的胚胎细胞偏析的时间和空间询问，以阐明基于CFNS发病机制的胚胎细胞偏析的时间和空间询问。通过在不同发育时间点和特定细胞群体产生Ephrin-B1镶嵌，我们发现Ephrin-B1在早期神经发育中独立调节细胞偏析，后来在颅面发育中，与面部形状的定量差异的出现相关。而在EFNB1杂合和嗜血突变体胚胎中，特异性的颅面形状变化在杂合和嗜血体胚胎中，杂合胚是定量更严重的影响，表明EFNB1镶嵌激发了功能表型的损失而不是具有新形态效应。值得注意的是，EFNB1的神经组织特异性破坏不会有助于CFNS Craniofacial疑似，但其在神经嵴细胞衍生的间充质中的破坏导致表型与广泛的损失非常相似。 Ephrin-B1可以用EphB1，EphB2和EphB3受体酪氨酸激酶结合和信号，但与CFN相关的信令合作伙伴是未知的。 EphB1等位基因系列的几何形态学分析; EphB2; EphB3突变体胚胎表明Ephb2和EphB3是介导EFNB1嗜合性表型的关键受体，但EphB1-3的完全丧失并未完全重新承载CFNS样EFNB1杂合子的严重程度。最后，通过产生EFNB1〜（+ /δ）; EphB1; EphB2; EphB3四重敲除小鼠，确定调节累积受体活性的调节程度如何影响颅面发育中的细胞偏析，发现ephb2和ephb3在颅面细胞分离中发挥着重要作用，EphB1对大脑中的细胞偏析更重要;令人惊讶的是，EPHB1-EPHB3的完全丧失并不完全消除细胞隔离。这些数据在一起推进了对CFNS疑难解的潜在病因和信令相互作用的理解。

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