Abstract
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.
Highlights
About 2–7% of all newborns have congenital anomalies
DMDD embryos harvested at E14.5 were imaged by high-resolution episcopic microscopy according to standard protocols (Mohun and Weninger, 2012a; Geyer et al, 2017a)
The complete absence of the hypoglossal nerve was observed in a total of 75 (15.2%) mutant embryos
Summary
About 2–7% of all newborns have congenital anomalies. Due to the multifactorial etiology, the prevalence varies greatly in different geographical regions (Eke et al, 2016; Bhide and Kar, 2018; EUROCAT, 2018). For Europe, it is reported with 256.3/10,000 births, with about 10% of all birth defects affecting the nervous system (Groen et al, 2017; EUROCAT, 2018; Morris et al, 2019). Due to technical advancements in prenatal diagnostic imaging, a large percentage of congenital anomalies, especially of the central nervous system (CNS) are diagnosed in utero. Congenital disorders of the CNS, which consists of the brain and spinal cord, can be caused by infectious diseases, environmental factors, and spontaneous or inherited mutations (Jurand, 1980; Verity et al, 2003). The key to optimizing existing diagnostic procedures and developing curative strategies for CNS defects is researching how the causative factors affect the formation, growth, and remodeling of the brain and spinal cord during early development. The most fruitful experimental approach has proved to be a careful analysis of the morphological, endocrine, and behavioral phenotypes of genetically modified model organisms, most commonly the mouse (Austin et al, 2004; Rosenthal and Brown, 2007; Guan et al, 2010; Waerzeggers et al, 2010; Desgrange et al, 2019; Ruberte et al, 2020)
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