Production of MHV-resistance mouse by embryo technology

为了利用胚胎技术培育出对小鼠肝炎病毒(MHV)具有抗性的小鼠株系，我们对小鼠对MHV的抗性机制进行了研究。SJL和BALB/c小鼠对MHV分别具有抵抗力和易感性。根据以下发现，我们推测MHV受体在这些小鼠中的表达导致了易感性的差异。1)MHV抗性由7号染色体上的单个常染色体基因控制，MHV受体基因也定位在该基因上。2)易感性高于耐药性的事实符合这样一个概念，即显性基因产物是使小鼠易感的宿主因素；MHV受体是候选之一。我们发现，在BALB/c中表达的受体MHVR1与MHV结合的效率是在SJL中表达的MHVR2的10-100倍，这可能是这两种小鼠之间不同易感性的原因。我们还利用BALB/c×SJL的F2代和回交后代，发现MHV抗性基因和MHV受体基因紧密连锁，在7号染色体上的距离为0.94 cM，这表明MHV抗性基因可能与MHV受体基因相同。为了检验这种可能性，目前正在进行用基因替换来取代MHVR1和MHVR2基因的实验。MHVR2被MHVR1取代的SJL和MHVR2被MHVR2取代的BALB/c的敏感性将得出我们的假设是正确的还是错误的结论。为了获得MHV抗性小鼠，目前正在进行通过基因打靶敲除MHV受体基因的实验。

We have studied the resistance mechanisms of mice to mouse hepatitis virus (MHV) in order to produce MHV-resistance mouse strain by embryo technology. SJL and BALB/c mice are resistant and susceptible to MHV, respectively. We speculated that the difference in susceptibility resulted from MHV receptor expressed in these mice from the following findings. 1) MHV resistance is controlled by a single autosomal gene on chromosome 7 on which MHV-receptor gene is also mapped. 2) The fact that susceptibility is dominant over the resistance fits the concept that a dominant gene product is a host factor to make mice susceptible ; MHV receptor is one of the candidates. We found that the receptor MHVR1 expressed in BALB/c was 10 to 100 fold more efficient for MHV binding than the MHVR2 expressed in SJL.This difference could be responsible for the different susceptibility between these mice. We have also found that MHV-resistance gene and MHV-receptor gene were tightly linked, within 0.94 cM distance on chromosome 7, by using F2 and backcrossed progenies between BALB/c x SJL.This suggests the possibility that MHV-resistance gene is identical to MHV-receptor gene. To examine such possibility, experiments are under progress to replace MHVR1 and MHVR2 genes by gene replacement. The susceptibility of SJL whose MHVR2 is replaced by MHVR1 as well as BALB/c whose MHVR1 is replaced by MHVR2 will conclude whether our hypothesis is right or not. To make MHV-resistance mice, experiment is currently in progress to knockout the MHV-receptor genes by gene targeting.