Polygenic resistance to mouse pulmonary adenomas.

Susceptibility to urethan-induced pulmonary adenomas (PA) in mice is under polygenic control. To analyze these traits in detail, we generated a set of recombinant inbred (RI) mouse strains, called SMXA, from an intercross between PA-susceptible A/J and resistant SM/J, and established a strain distribution pattern (SDP) table of 158 marker loci for SMXA RI strains. From the SDP table, it was possible to estimate the allele for 4 known PA susceptibility (Pas) loci in all members of SMXA RI strains. We compared combinations of Pas loci alleles with the data of number of PA induced by urethan. One of the RI strains, SMXA24, showed extremely low PA numbers, whereas they had the A/J-derived alleles at all 4 Pas loci. F1 hybrids of SMXA24 and A/J developed as few PA as SMXA24 on exposure to urethan. To confirm the hypothesis that SMXA24 has dominant PA resistance gene(s), we examined a backcross generation to A/J for multiplicity of PA. A preliminary genome scan followed by quantitative trait locus analysis revealed two resistance loci, one on mouse chromosome 11 (MMU11) (logarithm of odds [LOD] score 4.35) and another on MMU12 (LOD score 6.47). They were named Par1 and Par3, respectively. Both loci were epistatic to Pas1, the major susceptibility loci on MMU6. We next asked if such dominant resistance loci play some role in human lung cancer by studying possible loss of heterozygosity (LOH) at syntenic chromosomal segments in 79 human lung cancers, including 30 adenocarcinomas, 25 squamous cell carcinomas (SQ), and 24 small cell carcinomas (SCC). The map positions of Par1 and Par3 correspond to human 17q11-23 and 14q11-24. Of 30 adenocarcinomas, LOH was found in 53% at 17q and in 30% at 14q. For both SQ and SCC, LOH in 17q were about 10%, but LOH in 14q was about 30% to 42%. Therefore, a gene in 17q seemed to be selective for adenocarcinomas, probably at the level of the target cell. In contrast, another gene in 14q affected all 3 types of lung carcinomas, suggesting it is related to the progression of lung tumors in general. A comparative approach may provide useful information for understanding human cancers.

Loss of heterozygosity (LOH) at 17q and 14q in human lung cancers.

Our recent linkage study of urethane-induced pulmonary adenomas in SMXA RI strains of mouse revealed two host resistance genes, Par1 (chromosome 11) and Par3 (chromosome 12). The map positions of Par1 and Par3 correspond to human 17q11-23 and 14q11-24, based on synteny between mouse and human. In this study, we examined the loss of heterozygosity (LOH) in these two homologous human chromosomal regions in 30 primary lung adenocarcinoma samples with matched normal DNA. Using 15 highly polymorphic markers, two commonly deleted regions were identified on human chromosomes 14 and 17, respectively. At 17q21, nine (53%) of 17 informative tumors showed LOH between D17S588 and D17S518. On the other hand, at 14q11-12, seven (32%) of 22 informative tumors showed LOH at loci between D14S261 and D14S80. Subsequently, we examined 25 squamous cell carcinomas (SQ) and 24 small cell carcinomas (SCC). At 14q11-12, six (38%) of 16 informative SQ and five (42%) of 12 informative SCC showed LOH. In contrast, at 17q11-23, one (7%) of 15 informative SQ and two (14%) of 14 SCC showed LOH. Therefore, the gene on 17q seemed to affect selectively adenocarcinomas, whereas the other gene on 14q, all three types of lung carcinomas. These observations indicate that a comparative genetic analysis provides a promising approach to survey genes involved in multifactorial process of human lung carcinogenesis.

To be or not to be a T-lymphomas, that is determined by a dominant gene Tlsm-1 in mouse models.

A single dominant gene Tlsm-1 was found to determine the type of spontaneous lymphomas to be T in the cross between AKR/Ms and SL/Kh. Microsatellite analysis mapped Tlsm-1 at the position 61 cM from centromere of Chr. 7. Study of this segment of T-lymphoma prone AKXD Rl strains also showed association of Tlsm-1 with T-lymphomas. On the other hand, lymphoma latency was significantly shorten by a recessive gene lla of SL/Kh. By a quantitative trait analysis, lla was located in class II gene in MHC.

The origin of SL family mice.

The origin of SL family mice was studied by analyzing 100 microsatellite loci, the major histocompatibility complex, the Mx gene, murine leukemia provirus, and mammary tumor provirus. From the genetic profile of family members and their history, we assumed the existence of a proto-SL mouse, an ancestor of all SL family members. Many alleles were contributed to the proto-SL by the ancestors related to strains A2G and CF#1, and/or some wild mice. Among four existing family members, SL/Am and SL/Ni mice were almost identical and presumably closest to the proto-SL. The SL/Kh mouse was derived from a cross of the proto-SL and AKR mice, because SL/Kh mice inherited a considerable number of genes from AKR mice, the most outstanding of which were those of the provirus Emv-11 and Thy-1.1. The SL/QDj mice seemed to be a recombinant inbred strain between SL/Am and SL/Kh mice, because their alleles at all 100 microsatellite loci were shared by SL/Am or SL/Kh strains or both. All four SL family members shared the major histocompatibility complex haplotype q.

Monoclonal antibodies to a zinc-binding protein of rat Paneth cells.

Paneth cells are morphologically well characterized but their function has been not elucidated. Previously, we identified and purified a 90 KD zinc-binding protein (ZBPP-1) in rat intestine that was localized to Paneth cell granules, consistent with their high zinc content. To further elucidate the structure and function of ZBPP-1, we immunized Balb/c mice with purified ZBPP-1 and identified four independent monoclonal antibodies (MAb) producing MAb ZIP-1 (IgM), ZIP-2 (IgG1), ZIP-3 (IgM), and ZIP-4 (IgM). Immunohistochemistry (IHC) and immunoelectron microscopy (IEM) with these MAb showed positive staining of Paneth cell cytoplasmic granules. MAb ZBPP-1 also stained a population of mononuclear cells in the lamina propria of digestive tract mucosa and a few cells in spleen, presumably a subset of macrophages. These MAb will provide a useful tool to study the function of Paneth cells in human health and disease, since they cross-reacted with human intestinal Paneth cells and mucosal mononuclear cells.