Mov-13 Mice Research Articles

Retrovirus-induced lethal mutation in collagen I gene of mice is associated with an altered chromatin structure

The chromatin structure of the collagen α1(I) gene, which has been mutated by retrovirus insertion in Mov13 mice, was compared with that of the wild-type allele. Limited digestions with DNAase I revealed the presence of two hypersensitive sites in all normal cells analyzed, while a third site at 100 to 200 bp 5′ of the transcription start was detected only in cells synthesizing collagen α1(I) mRNA. This transcription-associated site was not present in chromatin of the mutant allele, while the two other hypersensitive sites, one of which is located close to the provirus, were not changed by the virus integration. Our results suggest that the virus insertion in Mov13 mice may prevent the developmentally regulated appearance of a transcription-associated hypersensitive site, thereby interfering with proper activation of the gene during embryonic development.

Tolerance to viral antigens in Mov-13 mice carrying endogenized moloney-murine leukemia virus

In virus-positive (V +) C57BL/6 Mov-13 mice, Moloney-murine leukemia virus (M-MuLV) is integrated into the germ line and expressed early in lymphoid and nonlymphoid organs. The pattern of immune reactivity to viral antigens in these mice was studied and compared to that of their virus-negative (V −) counterparts. Using a radioimmunobinding or -precipitation assay, V − mice showed good antibody production after challenge with Moloney-murine sarcoma virus (M-MSV), but no antibodies were detected in V + mice. Moreover, Mov-13 V + mice failed to generate virus-specific cytotoxic T lymphocytes (CTL) in secondary mixed-leukocyte tumor cell culture (MLTC) while V − mice showed a strong cytotoxic response. This lack of activity in mass V + cultures was due to a very low frequency of CTL precursors which did not increase following in vivo challenge with M-MSV or in vitro stimulation with MBL-2 Moloney leukemia cell line. These findings indicate that early M-MuLV activation in Mov-13 V + mice induces a state of tolerance to viral antigens involving both the humoral and cellular immune responses and related to the high incidence of T-cell lymphomas.

Chromosomal position and activation of retroviral genomes inserted into the germ line of mice

The exogenous Moloney leukemia virus (M-MuLV) was inserted into the germ line of mice by exposing embryos to virus at different stages of embryogenesis. Mice derived from exposed embryos were mosaics with respect to integrated virus. Nine new substrains, designated Mov-5 to Mov-13, were derived, each of which carries a single M-MuLV genome at a different chromosomal position in its germ line. Four substrains, Mov-1 to Mov-4, were derived previously. Restriction enzyme analyses demonstrated that, with the exception of Mov-4 and Mov-6 mice, no major rearrangements or deletions have occurred in the integrated proviral genomes. Infectious virus is not activated in the majority of substrains (Mov-4 to Mov-8 and Mov-10 to Mov-12), whereas the other mice develop viremia. A detailed comparison between Mov-1 and Mov-13 mice demonstrated that the time of virus activation is different. Mov-13 mice activate infectious virus during embryogenesis, leading to a distinct pattern of virus expression in all tissues of the adult, but the viral genome in Mov-1 mice is activated only during the first two weeks after birth, leading to virus expression predominantly in lymphatic organs. Together with previous observations, at least four different phenotypes of virus expression—that is, early virus activation during embryogenesis, virus activation after birth, virus activation late in life and no expression of infectious virus at all—can be distinguished among the 13 substrains. Our results suggest that the chromosomal region at which a viral genome is integrated influences its expression during development and differentiation.