An essential step in researching human central nervous system disorders is the search for appropriate mouse models that can be used to investigate both genetic and environmental factors underlying the etiology of such conditions. Identification of murine models relies upon detailed pre- and post-natal phenotyping, since profound defects are not only the result of gross malformations, but can be the result of small or subtle morphological abnormalities. The difficulties in identifying such defects is compounded by the finding that many mouse lines show quite variable penetrance of phenotypes. As a result, without analysis of large numbers, such phenotypes are easily missed. Indeed for null mutations, around one third have proved to be pre- or perinatally lethal, their analysis resting entirely upon phenotyping of accessible embryonic stages. To simplify identification of potentially useful mouse mutants, we have conducted three dimensional phenotype analysis of approximately 500 homozygous null mutant embryos, produced from targeting a variety of mouse genes and harvested at embryonic day 14.5 as part of the “Deciphering the Mechanisms of Developmental Disorders” (www.dmdd.org) program. We have searched for anatomical features which have the potential to serve as biomarkers for central nervous system (CNS) defects in such genetically modified lines. Our analysis identified two promising biomarker candidates. Hypoglossal nerve abnormalities (absent, thin and abnormal topology) and abnormal morphology or topology of head arteries are both frequently associated with the full spectrum of morphological CNS defects, ranging from exencephaly to more subtle defects such as abnormal nerve cell migration. Statistical analysis confirmed that hypoglossal nerve abnormalities (especially those scored absent or thin) indeed showed a significant correlation with other CNS defect phenotypes. These results demonstrate that null mutant lines showing hypoglossal nerve abnormalities are also highly likely to produce CNS defects whose identification may be difficult as a result of morphological subtlety or low genetic penetrance.

中文翻译：

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舌下神经异常作为产生胚胎致死后代的小鼠系中枢神经系统缺陷的生物标志物


研究人类中枢神经系统疾病的一个重要步骤是寻找合适的小鼠模型，用于研究此类疾病病因学背后的遗传和环境因素。小鼠模型的鉴定依赖于详细的产前和产后表型分析，因为严重缺陷不仅是严重畸形的结果，而且可能是微小或细微的形态异常的结果。由于发现许多小鼠品系显示出相当可变的表型外显率，因此识别此类缺陷变得更加困难。因此，如果不进行大量分析，这种表型很容易被遗漏。事实上，对于无效突变，大约三分之一已被证明是产前或围产期致死的，他们的分析完全依赖于可及胚胎阶段的表型分析。为了简化潜​​在有用的小鼠突变体的鉴定，我们对大约 500 个纯合无效突变体胚胎进行了三维表型分析，这些胚胎是针对多种小鼠基因产生的，并在胚胎第 14.5 天收获，作为“破译发育障碍机制”的一部分(www.dmdd.org) 计划。我们在此类转基因品系中寻找有可能作为中枢神经系统（CNS）缺陷生物标志物的解剖特征。我们的分析确定了两种有前途的候选生物标志物。舌下神经异常（拓扑缺失、薄弱和异常）和头动脉形态或拓扑异常都经常与中枢神经系统形态学缺陷相关，范围从脑外畸形到更微妙的缺陷，例如异常神经细胞迁移。 统计分析证实，舌下神经异常（尤其是那些缺失或稀疏的神经异常）确实与其他中枢神经系统缺陷表型显着相关。这些结果表明，显示舌下神经异常的无效突变系也极有可能产生中枢神经系统缺陷，由于形态学的微妙性或遗传外显率低，这些缺陷的识别可能很困难。