Gunn T M, Juriloff D M, Harris M J
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Teratology. 1995 Aug;52(2):101-8. doi: 10.1002/tera.1420520206.
The SELH/Bc mouse strain (SELH) has a high frequency of the lethal neural tube closure defect, exencephaly, in newborns and embryos. Previous work has shown that all SELH mouse embryos have an abnormal mechanism of rostral neural tube closure. They lack initiation of contact and fusion of the cranial neural tube at the prosencephalon/mesencephalon boundary [Closure 2), and undergo closure by extension of a more rostral site of fusion. This process fails in 10-20% of embryos, where the mesencephalic folds remain unelevated, resulting in exencephaly. Previous work has also shown that the cause of liability to exencephaly in SELH mice is multigenic, involving a small number of loci. The purpose of the present study was to test the hypothesis that the genes causing the lack of Closure 2 also cause the liability to exencephaly in SELH, by observation of their joint transmission from genetically segregating animals. A concurrent mapping study provided the necessary genetic material, a segregating F2 generation from a cross of SELH with the normal LM/Bc strain. The genetic liability to exencephaly transmitted by individual F2 sires had been measured by the frequencies of exencephalic day 14 embryos they produced in test-crosses with SELH females. A selected subset of 13 of these test-crossed F2 sires was bred with a second set of SELH females, and the embryos were examined earlier, during the period of neural tube closure, on days 8 and 9 of gestation, to determine the presence of Closure 2. Six F2 sires were among the highest exencephaly producers (6-11%), six were among the lowest (0%), and one was intermediate (5%). Among embryos at the appropriate stage for scoring, the presence of Closure 2 was observed to be inversely correlated with the later risk of exencephaly, being present in 93% (71/76) from the low-risk sires and 35% (36/103) from the high-risk sires. In each case, the remaining embryos had a closure mechanism like that of SELH embryos. Among the individual intermediate- and high-risk sires, there was also a clear correlation between the frequency of exencephaly in older embryos and the frequency of lack of Closure 2 in early embryos (rs = 0.88; P < 0.05). This study demonstrates that high liability to exencephaly and absence of Closure 2 are genetically transmitted together. That is, the cause of the lack of Closure 2 in SELH mice is shown to be also the probable cause of the high liability to exencephaly.
SELH/Bc小鼠品系（SELH）的新生小鼠和胚胎中，致死性神经管闭合缺陷——无脑畸形的发生率很高。先前的研究表明，所有SELH小鼠胚胎的吻侧神经管闭合机制均异常。它们在端脑/中脑边界处（闭合2）缺乏颅神经管的接触起始和融合，而是通过更靠前的融合位点延伸来完成闭合。这一过程在10%-20%的胚胎中失败，中脑褶皱未抬起，导致无脑畸形。先前的研究还表明，SELH小鼠发生无脑畸形的原因是多基因的，涉及少数基因座。本研究的目的是通过观察基因分离动物中导致闭合2缺失的基因的联合传递，来检验该假设，即导致闭合2缺失的基因也是SELH小鼠发生无脑畸形易感性的原因。一项同步的定位研究提供了必要的遗传材料，即SELH与正常LM/Bc品系杂交产生的分离F2代。通过与SELH雌性小鼠进行测交，F2代父本所产生的第14天无脑畸形胚胎的频率，来衡量个体F2代父本传递无脑畸形的遗传易感性。从这些测交的F2代父本中挑选出13个组成一个子集，与另一组SELH雌性小鼠交配，并在神经管闭合期，即妊娠第8天和第9天，更早地检查胚胎，以确定是否存在闭合2。6个F2代父本属于无脑畸形发生率最高的组（6%-11%），6个属于最低的组（0%），1个属于中间组（5%）。在适合评分的胚胎阶段，观察到闭合2的存在与后期无脑畸形风险呈负相关，低风险父本的胚胎中93%（71/76）存在闭合2，高风险父本的胚胎中35%（36/103）存在闭合2。在每种情况下，其余胚胎具有与SELH胚胎类似的闭合机制。在个体中间风险和高风险父本中，较老胚胎的无脑畸形频率与早期胚胎中闭合2缺失的频率之间也存在明显的相关性（rs = 0.88；P < 0.05）。本研究表明，无脑畸形的高易感性和闭合2的缺失是一起遗传传递的。也就是说，SELH小鼠中闭合2缺失的原因也被证明可能是无脑畸形高易感性的原因。
