Hypoglossal Nerve Abnormalities as Biomarkers for Central Nervous System Defects in Mouse Lines Producing Embryonically Lethal Offspring.
Hypoglossal Nerve Abnormalities as Biomarkers for Central Nervous System Defects in Mouse Lines Producing Embryonically Lethal Offspring.
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DOI：
10.3389/fnana.2021.625716
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发表时间：
2021
影响因子：
2.9
通讯作者：
Weninger WJ
中科院分区：
文献类型：
--
作者：
Reissig LF;Seyedian Moghaddam A;Prin F;Wilson R;Galli A;Tudor C;White JK;Geyer SH;Mohun TJ;Weninger WJ
研究人类中枢神经系统（CNS）疾病的一个重要步骤是寻找合适的小鼠模型，可用于研究这些疾病的病因学的遗传和环境因素。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大体畸形的结果，也可能是小的或细微的形态学异常的结果。由于发现许多小鼠品系表现出相当可变的表型突变率，因此鉴定这种缺陷的难度更大。因此，如果不对大量数据进行分析，这些表型很容易被遗漏。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接近的胚胎阶段的表型。为了简化潜在有用的小鼠突变体的鉴定，我们对大约500个纯合无效突变胚胎进行了三维表型分析，通过靶向多种小鼠基因产生，并在胚胎第14.5天收获，作为“破译发育障碍机制”www.example.com计划的一部分www.dmdd.org.uk。我们已经搜索了有可能作为生物标志物的CNS缺陷，在这样的遗传修饰线的解剖特征。我们的分析确定了两个有希望的生物标志物候选者。舌下神经（HGN）异常（缺失、变细和异常拓扑）和头部动脉的异常形态或拓扑通常与全谱形态CNS缺陷相关，从露脑到更细微的缺陷，如异常神经细胞迁移。统计分析证实，HGN异常（尤其是那些评分缺失或薄）确实显示出与CNS缺陷表型的显著相关性。这些结果表明，显示HGN异常的无效突变株系也极有可能产生CNS缺陷，由于形态学上的细微差别或低遗传变异率，其鉴定可能是困难的。
An essential step in researching human central nervous system (CNS) 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 are compounded by the finding that many mouse lines show quite a 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 the 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.uk program. We have searched for anatomical features that have the potential to serve as biomarkers for CNS defects in such genetically modified lines. Our analysis identified two promising biomarker candidates. Hypoglossal nerve (HGN) 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 HGN abnormalities (especially those scored absent or thin) indeed showed a significant correlation with CNS defect phenotypes. These results demonstrate that null mutant lines showing HGN abnormalities are also highly likely to produce CNS defects whose identification may be difficult as a result of morphological subtlety or low genetic penetrance.
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影响因子：
64.8
作者：
Perez-Garcia V;Fineberg E;Wilson R;Murray A;Mazzeo CI;Tudor C;Sienerth A;White JK;Tuck E;Ryder EJ;Gleeson D;Siragher E;Wardle-Jones H;Staudt N;Wali N;Collins J;Geyer S;Busch-Nentwich EM;Galli A;Smith JC;Robertson E;Adams DJ;Weninger WJ;Mohun T;Hemberger M
通讯作者：
Hemberger M
影响因子：
2.4
作者：
Reissig, Lukas F.;Herdina, Anna Nele;Weninger, Wolfgang J.
通讯作者：
Weninger, Wolfgang J.
影响因子：
2.8
作者：
Becker, K.;Jaehrling, N.;Dodt, H. -U
通讯作者：
Dodt, H. -U
影响因子：
5.3
作者：
Dodt, Hans-Ulrich;Saghafi, Saiedeh;Niendorf, Axel
通讯作者：
Niendorf, Axel
影响因子：
2.5
作者：
JURAND, A
通讯作者：
JURAND, A