Interactions between Shh pathway regulators and fetal alcohol exposure in mice

无前脑畸形(HPE)是一种常见的前脑和面中部出生缺陷，既有环境因素，也有环境因素。 遗传因素。环境因素之一是孕妇在怀孕早期饮酒。在……里面 此外，已在人类HPE中发现了Sonic hedgehog(Shh)信号通路的突变。这个 突变携带者的HPE表型是高度可变的，影响的范围从 前脑和面中部有严重的缺陷，没有临床表现。造成这种差异的原因是 已知，但也可能需要的因素包括额外的遗传影响或环境暴露 在胎儿发育过程中。基因-环境的相互作用很可能与一种复杂的疾病有关，比如 HPE；然而，针对这一点的模型很少。CDO和Boc是结合Shh和调节Shh的细胞表面蛋白 发育中胚胎特定区域的信号通路强度。CDO突变小鼠表现为HPE 菌株特有的严重程度：129/Sv背景上的突变体表现出非常轻微的低频率HPE，而 C57BL/6背景上的突变体在高频下表现出更严重的形式。BOC突变小鼠没有 显性效应，但129/Sv CDO；Boc双突变体表现出严重的颅面部HPE特征。我们报道说 129/Sv小鼠对乙醇诱导的HPE具有抵抗力；然而，暴露在乙醇诱导的HPE中的129/Sv CDO突变胚胎中有80% 子宫到乙醇表现出很强的颅面HPE，与CDO有惊人的相似之处；Boc双突变体。 此外，乙醇处理的CDO突变体的前脑Shh表达显著减少。 胚胎。因此，CDO的丧失和胎儿酒精暴露可以协同作用产生HPE；这一事实，再加上 乙醇处理的CDO突变胚胎与CDO如此相似；Boc双突变，认为CDO和CDO的丢失 乙醇暴露对Shh信号转导有协同作用。四肢和手指的缺陷也与 人胎儿酒精暴露和宫内C57BL/6胚胎乙醇暴露可导致 四肢和脚趾的后方。所有肢体和手指的后方花纹都需要Shh。损失 中国银行，但不是CDO，会在遗传敏感的背景下导致严重的手指缺陷。据推测， 与129/Sv CDO突变小鼠和HPE类似，129/Sv Boc突变小鼠将对乙醇致敏 四肢/手指畸形。关于乙醇如何扰乱已知的监管机构的信息相对较少 乙醇处理的C57BL/6和129/Sv小鼠的肢体/手指模式和发育遗传学分析 阐明了这一过程。本方案的目的是：1)分析129/Sv CDO中乙醇诱导的HPE 突变小鼠；2)确定乙醇诱导前脑Shh表达下调的机制 129/Sv CDO突变小鼠；3)分析Shh通路在乙醇诱导的小鼠脑损伤中的作用。 肢体/指甲图案。这些研究包括对一个新开发的基因-环境模型的分析。 在常见的出生缺陷中，明确的发育突变和乙醇之间的相互作用。这样的信息 可能会对公众健康产生重要影响，并最终可能有助于对突变携带者的咨询。

Holoprosencephaly (HPE) is a common birth defect of the forebrain and midface with both environmental and genetic causes. Among the environmental factors is maternal alcohol consumption during early pregnancy. In addition, mutations in the Sonic hedgehog (Shh) signaling pathway have been identified in human HPE. The HPE phenotype of mutation carriers is highly variable, with the spectrum of effects ranging in a continuum from severe defects in the forebrain and midface to no clinical manifestation. The reason for this variability is un- known, but factors that may also be required include additional genetic influences or environmental exposures during fetal development. Gene-environment interactions are likely to be involved in a complex malady like HPE; however, there are few models for this. Cdo and Boc are cell surface proteins that bind Shh and regulate pathway signaling strength in specific regions of the developing embryo. Cdo mutant mice display HPE with strain-specific severity: mutants on the 129/Sv background show very mild HPE with low frequency, while mutants on the C57BL/6 background show more severe forms at high frequency. Boc mutant mice are without overt effect, but 129/Sv Cdo;Boc double-mutants display severe craniofacial HPE features. We report that 129/Sv mice are resistant to ethanol-induced HPE; however, 80% of 129/Sv Cdo mutant embryos exposed in utero to ethanol display strong craniofacial HPE and bear a striking resemblance to Cdo;Boc double mutants. Furthermore, there is a strong reduction of Shh expression in the forebrain of ethanol-treated Cdo mutant embryos. Loss of Cdo and fetal ethanol exposure therefore synergize to produce HPE; this fact, plus that ethanol-treated Cdo mutant embryos are so similar to Cdo;Boc double-mutants, argues that loss of Cdo and ethanol exposure have a synergistic effect on Shh signaling. Limb and digit defects are also associated with human fetal alcohol exposure, and in utero ethanol exposure of C57BL/6 embryos results in malformations of the posterior aspects of limbs and digits. Shh is required for all posterior patterning of limbs and digits. Loss of Boc, but not Cdo, results in severe digit defects on a genetically-sensitized background. It is hypothesized that, similar to 129/Sv Cdo mutant mice and HPE, 129/Sv Boc mutant mice will be sensitized to ethanol-induced limb/digit anomalies. There is relatively little information available on how ethanol disrupts the known regulators of limb/digit patterning, and developmental genetic analyses of ethanol-treated C57BL/6 and 129/Sv mice will shed light on this process. The aims of this proposal are: 1) to analyze ethanol-induced HPE in 129/Sv Cdo mutant mice; 2) to identify mechanisms of ethanol-induced down-regulation of Shh expression in the forebrains of 129/Sv Cdo mutant mice; and 3) to analyze the role of the Shh pathway in ethanol-induced defects in limb/digit patterning. These studies involve analysis of a newly developed model of gene-environment interaction between a defined developmental mutation and ethanol in a common birth defect. Such information may have important public health impact and could ultimately aid in the counseling of mutation carriers.