Production of MHV-resistance mouse by embryo technology

本文研究了小鼠对小鼠肝炎病毒（MHV）的抗性机制，以期通过胚胎技术产生抗MHV的小鼠品系。SJL和BALB/c小鼠分别对MHV有抗性和易感。根据以下发现，我们推测这些小鼠的易感性差异是由MHV受体表达引起的。1) MHV抗性由7号染色体上的一个常染色体基因控制，该基因上也定位有MHV受体基因。2)易感性高于抗性的事实符合显性基因产物是使小鼠易感的宿主因素的概念；MHV受体是候选之一。我们发现BALB/c中表达的MHVR1受体与MHV结合的效率是SJL中表达的MHVR2的10到100倍。这种差异可能是导致这些小鼠之间易感性不同的原因。利用BALB/c x SJL的F2回交后代，我们还发现mhv抗性基因和mhv受体基因在7号染色体上的0.94 cM距离内紧密连锁。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，正在进行通过基因替换替换MHVR1和MHVR2基因的实验。MHVR2被MHVR1取代的SJL和MHVR1被MHVR2取代的BALB/c的易感性将决定我们的假设是否正确。为了制造抗mhv小鼠，目前正在进行基因靶向敲除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.