Interactions between Shh pathway regulators and fetal alcohol exposure in mice

Shh 通路调节因子与小鼠胎儿酒精暴露之间的相互作用

基本信息

批准号：
8516408
负责人：
Robert S. Krauss
金额：
$ 35.3万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516408
关键词：
129/Sv Mouse Alcohol consumption Alobar Holoprosencephaly Animal Model Anterior nares Apoptosis Binding C57BL/6 Mouse Cell Surface Proteins Clinical Complex Congenital Abnormality Counseling Defect Development Digit structure Down-Regulation Ectoderm Embryo Employee Strikes Environmental Exposure Environmental Risk Factor Erinaceidae Ethanol Etiology Face Failure Fetal Alcohol Exposure Fetal Development Frequencies Genes Genetic Genetic Predisposition to Disease Genetic Variation Goals Holoprosencephaly Human Impairment Light Limb Bud Limb structure Microforms Modeling Mus Mutant Strains Mice Mutation Outcome Pattern Penetrance Phenotype Population Pregnancy Process Prosencephalon Protein Binding Public Health Reporting Resistance Role Severities Signal Pathway Signal Transduction Sonic Hedgehog Pathway Staging Structure Teratogens Time Ursidae Family Zebrafish alcohol exposure craniofacial developmental genetics gene environment interaction genetic analysis genetic pedigree in utero insight malformation mouse model mutant mutation carrier palatogenesis receptor smoothened signaling pathway

项目摘要

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.

全脑脑（HPE）是前脑的常见出生缺陷，环境和环境和中间。遗传原因。在环境因素中，孕妇在怀孕初期的饮酒量。在此外，在人类HPE中已经确定了声音刺猬（SHH）信号通路中的突变。这突变载体的HPE表型是高度可变的，其效应范围在连续体中。前脑和中间的严重缺陷，没有临床表现。这种可变性的原因是已知，但也可能需要的因素包括其他遗传影响或环境暴露在胎儿发育期间。基因环境的相互作用可能与复杂的疾病有关 hpe;但是，很少有模型。 CDO和BOC是结合SHH并调节的细胞表面蛋白发育胚的特定区域的途径信号强度。 CDO突变小鼠展示HPE 特异性严重程度：129/SV背景上的突变体显示出非常轻度的HPE，而频率低，而 C57BL/6背景上的突变体在高频下显示出更严重的形式。 BOC突变小鼠没有明显的效果，但129/SV CDO; BOC双突出体显示出严重的颅面HPE特征。我们报告了 129/SV小鼠对乙醇诱导的HPE具有抗性；但是，暴露于129/SV CDO突变胚胎中的80％子宫至乙醇表现出强大的颅面HPE，并且与CDO; BOC双突变体具有惊人的相似之处。此外，在经乙醇处理的CDO突变体的前脑中，SHH表达的大幅度降低胚胎。 CDO和胎儿乙醇暴露的损失因此协同产生HPE；这个事实，加上经乙醇处理的CDO突变胚胎与CDO如此相似； BOC双重突变剂，认为CDO和CDO的损失乙醇暴露对SHH信号传导具有协同作用。肢体和数字缺陷也与人类胎儿酒精暴露，在C57BL/6胚胎的子宫乙醇暴露中导致畸形四肢和数字的后方方面。所有四肢和数字的后部模式都需要SHH。损失 BOC（但不是CDO）在遗传敏感的背景下导致严重的数字缺陷。假设，类似于129/SV CDO突变小鼠和HPE，129/SV BOC突变小鼠将被敏感到乙醇诱导的肢体/数字异常。关于乙醇如何破坏已知调节器的信息相对较少的信息可用肢体/数字模式以及经乙醇处理的C57BL/6和129/SV小鼠的发育遗传分析将阐明了这个过程。该提案的目的是：1）分析129/SV CDO中乙醇诱导的HPE 突变小鼠； 2）确定乙醇诱导的前脑中SHH表达下调的机制 129/SV CDO突变小鼠； 3）分析SHH途径在乙醇引起的缺陷中的作用肢体/数字图案。这些研究涉及对新开发的基因环境模型的分析常见的先天缺陷中定义的发育突变与乙醇之间的相互作用。这样的信息可能会产生重要的公共卫生影响，并最终可能有助于突变载体的咨询。