An Impaired Breeding Phenotype in Mice with a Genetic Deletion of Beta-2 Microglobulin and Diminished MHC Class I Expression: Role in Reproductive Fitness

Joanne C Cooper; Gillian B Dealtry; Mohamed Abdelrahman Ahmed; Petra C Arck; Burghard F Klapp; Sandra M Blois; Nelson Fernández

doi:10.1095/biolreprod.106.057125

. 2007 Aug 1;77(2):274–279. doi: 10.1095/biolreprod.106.057125

An Impaired Breeding Phenotype in Mice with a Genetic Deletion of Beta-2 Microglobulin and Diminished MHC Class I Expression: Role in Reproductive Fitness^¹

Joanne C Cooper ^4,³, Gillian B Dealtry ^5,³, Mohamed Abdelrahman Ahmed ⁶, Petra C Arck ⁷, Burghard F Klapp ⁷, Sandra M Blois ^7,⁸, Nelson Fernández ^8,²

PMCID: PMC7110103 PMID: 17442853

Abstract

Beta-2 microglobulin (B2M) plays a pivotal role in the biology of mammals, including its association with major histocompatibility complex (MHC) Class I gene products. The latter molecules have been shown to affect reproduction in both mice and humans, although the exact mechanism is still unknown. Here we report the results of a longitudinal study of the reproductive performance of a genetically modified B2m deficient mouse strain with low MHC Class I expression. Our data show that this mouse strain has an impaired reproductive performance. However, the mice superovulate well and show a normal estrous cycle. Breeding studies from crosses between the transgenic mice and the wild-type parental strain show that B2m deficient mice have a significantly lower frequency of mating than the control B2m^+/+ mice. In addition, the litter size and weaning success of B2m deficient mice were lower than the control. Perinatal lethality of the B2m deficient offspring was also inflicted by cannibalism of the young pups by the B2m deficient female. The impaired breeding phenotype (IBP) can be reversed by reintroducing the B2m gene in F1 heterozygous B2m^+/− animals; thus the presence of B2M confers a normal breeding pattern. The acquisition of an impaired breeding phenotype (IBP) as a result of the knockout of B2m directly implicates B2M in the reproductive cycle of mice and raises the possibility of an effect of B2M on the reproduction of other mammals.

Keywords: beta-2 microglobulin, female reproductive tract, fetus, MHC (H-2), odor discrimination, odortypes

Introduction

Beta-2 microglobulin (B2M) is the product of a single copy, low-polymorphic gene, which encodes a 12 000 Dalton nonglycosylated protein belonging to the immunoglobulin superfamily. The mouse B2m gene is di-allelic, encoding two proteins that differ at a single amino acid residue [1]. B2M exists as a soluble product in serum, and, since its gene lacks a transmembrane coding exon, it is released into solution from a variety of cells. The B2M protein forms physical associations with a number of molecules; these include major histocompatibility complex (MHC) Class I and cluster of differentiation 1 (CD1) [2]. B2M also associates with the Fc receptor of the placenta, where it allows trans-placental transport of IgG from the mother to the foetus [3], and associates with the Fc receptor of neonatal gut epithelium for transport of IgG in the gut epithelium [4]. The major histocompatibility complex-related Fc receptor (FCGRT) is also implicated in IgG homeostasis in the adult [5]. In addition, it participates in the regulation of albumin [6] and in HFE (iron transport) [7].

The B2M protein plays a pivotal role in the biosynthesis of MHC class I molecules, controlling assembly, peptide binding, and cell-surface expression [8]. The majority of the fully assembled mature MHC class I molecules exist as an assembled complex with B2M, with the exception of free Class I heavy chains of the H-2^b haplotype [9]. Thus B2M is an essential molecule in the process of antigen presentation in the adaptive immune system.

One dramatic effect of the deletion of B2m in homozygous knockout mice is that cell-surface and cytoplasmic expression of MHC Class I molecules are significantly reduced [10], leading to a reduction of the CD4⁻ CD8⁺ subpopulation of mature T cells [11, 12]. As a consequence, adult mice are susceptible to some parasitic diseases such as Trypanosoma cruzi infections [13], but not leishmaniasis [14] or blood-stage malarial infections [15]. These mice also have delayed viral clearance and increased mortality after Theiler virus infection [16]; and are susceptible to mouse hepatitis virus with the infected mice being more susceptible to acute hepatitis and encephalitis [17]. In rheovirus infection, B2m^−/− mice showed enhanced intestinal mucosal and systemic immune responses by elevated IgG and IgA [18]. However, quite remarkably, in the absence of infections, a B2m^−/− strain has a healthy phenotypic appearance, develops well into adulthood and has a normal life span, despite a deficiency in iron metabolism [19].

Of critical importance is the finding that B2m knockout mice are distinguishable by scent from identical mice with an intact B2m gene [20], thus supporting the notion that MHC products are important in providing olfactory recognition and odortypes in rodents [21–43] and humans [44–49].

In the course of experiments designed to generate mouse embryos for gene transcription studies and immuno-detection of MHC products [50–51], we consistently observed an impaired reproductive capacity in the B2m deficient mice. We report this observation here, which we have termed impaired breeding phenotype (IBP), and discuss the biological implications of such a defect.

Materials and Methods

Mouse Strains and Crosses

All the mice in this study were of the C57BL/6 genetic background. Our transgenic founding colony consisted of females and males, all homozygous B2m^−/− on the C57BL/6 background [11]. Mice from this colony, the wild-type parental strain (B2m^+/+ C57BL/6) and heterozygous offspring of crosses between these two strains were used. The frequency of mating was defined by the appearance of postcopulatory vaginal plugs after overnight pairing of single B2m^−/−, B2m^+/+, or B2m^−/+ males with groups of up to three females of B2m^−/−, B2m^−/+, or wild-type B2m^+/+ genotypes. Breeding data were collected over a period of 1 1/2 years from age-matched crosses generated between B2m^−/− × B2m^−/− (20 pairs of mice; breeding period: 6–32 weeks of age); B2m^+/+ × B2m^+/+ (10 pairs of mice; breeding period: 6–32 weeks); B2m^+/+ × B2m^−/− (8 pairs of mice; breeding period: 6–24 weeks); B2m^−/− × B2m^+/+ (10 pairs of mice; breeding period: 6–28 weeks) and B2m^+/− × B2m^+/− (33 pairs of mice; breeding period: 6–24 weeks). Once a mouse was seen to be pregnant, the male was removed from the breeding pair and the female was housed alone until her pups were weaned. Thus stress due to overcrowding or the presence of the male was avoided. All procedures described within were reviewed and approved by the Institutional Animal Care and Use Committees of the University of Essex and were performed in accordance with the Guiding Principles for the Care and Use of Laboratory Animals.

Mouse Husbandry

In order to avoid shifts in the circadian rhythm and hence the estrous cycle, all mice were bred and maintained in a temperature-, humidity-, and light-controlled room (lights-on 700 to 2000 h) and housed in identical cages (University of Essex, Biological Services Unit). Mice were allowed food (laboratory diet RM3 [E], SDS Ltd., Witham, Essex) and water ad libitum. Our mouse colony was free of mouse hepatitis virus.

Cannibalism

This behavioral characteristic was defined as a defect in the normal care of the newborn pups, reflected in visible physical damage to the pups and detachment of the mother from the newborn litter.

Superovulation Procedure

Adult (6–8 weeks of age) females were stimulated with 5 IU eCG (Folligon, Intervet UK Ltd., Milton Keynes, UK) and 5 IU hCG intraperitoneal (Pregnyl, Organon Laboratories Ltd., Cambridge, UK) at 1700 h, 48 h apart, to induce superovulation. The control group consisted of naturally cycling females of the same strain (without stimulation).

Determination of Estrous Cycle

The estrous cycle was studied using cells removed by gentle mechanical disruption following vaginal washes, stained with hematoxylin/eosin solution and analyzed by light microscopy. Samples were classified as follows: proestrus, nucleated epithelial cells with occasional leukocytes and small degenerative nuclei cells; estrus, numerous cells from squamous epithelium and small epithelial cells; metestrus, numerous leukocytes and small cornified epithelial cells, and diestrus, mucus and nucleated cells.

Data Analysis

Data are expressed as means and SEM. Statistical significance between groups was tested using chi-square test for homogeneity and Mann-Whitney U-test for two proportions. Significance was set at P ≤ 0.05 (*), P ≤ 0.01(**), P ≤ 0.001(***).

Results

Reproductive Fitness

A longitudinal study designed to quantify the reproductive fitness of the B2m deficient mouse was conducted. Due to a steady depletion of breeding stocks of the transgenic mice, we began to outbreed the transgenic B2m deficient C57BL/6 mice with wild-type C57BL/6 mice to produce B2m heterozygous stocks. The F1 litters from these mating were then crossed to replenish the B2m negative mice. The data show that the B2m deficient mice have a lower number of litters born than the control group of C57BL/6 mice (P < 0.05). The total number of pups born to B2m deficient mice was significantly lower than the number born to the control mice (P < 0.001) (Table 1).

Table 1.

Reproductive fitness of the B2m deficient mouse.

Mating combination	No. of litters born^a	No. of pups born^a
B2m ^+/+ female × B2m^+/+ male	43 ± 2	315 ± 10
B2m ^−/− female × B2m^−/− male	31 ± 4^*	147 ± 7^***
B2m ^−/− female × B2m^+/+ male	34 ± 6	134 ± 6^***
B2m ^+/+ female × B2m^−/− male	35 ± 7	124 ± 9^***
B2m ^−/+ female × B2m^−/+ male	39 ± 4	400 ± 19^*

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^{^a}

Values are presented as mean ± SEM.

P < 0.05 and

^***

P < 0.001 versus wild-type females analyzed by Student t-test.

Postnatal Mortality

Analysis of postnatal mortality as determined by natural death (not cannibalized animals) (Fig. 1), revealed that the B2m homozygous deficient mice (B2m^−/−) had a similar proportion of postnatal natural deaths (29.9%) to the C57BL/6 B2m^+/+ homozygous control mice (29.8%), although the control group had a higher total number of pups born. Interestingly, overall postnatal natural death declined when a B2m^+/+ female was crossed with a B2m^−/− male (12.9%) or a B2m^−/− female was crossed with a B2m^+/+ male (11.8%) (P < 0.01). This decline was even greater when the heterozygous B2m^+/− mouse strain was crossed with identical B2m^+/− mice (6.8%) (P < 0.001), suggesting that crossing mice heterozygous for B2m confers a higher rate of survival of the offspring. Since the progeny of this cross will include genotypes of B2m^+/+, B2m^+/−, or B2m^−/−, this finding suggests that the maternal genotype may be an important determining factor rather than the embryo genotype.

Cannibalism

We then examined the postnatal mortality rate by cannibalism (Fig. 2) and observed that pups born from homozygous B2m^−/− parents exhibited a significantly higher rate of death than pups born to the B2m^+/+ mice (31.3% and 9.2% of total pups born respectively [P < 0.001]). The presence of the B2m gene appears to confer a higher survival rate since the homozygous B2m^+/+ female mice crossed with the homozygous B2m^−/− males exhibited a low cannibalism death rate (2.4%). The reverse mating combination that is homozygous B2m^−/− female mice crossed with the homozygous B2m^+/+ males also exhibited a low cannibalism death rate (2.1%). Similarly, the mating of B2m^+/− heterozygous individuals showed a lower death rate by cannibalism (0.5% [P < 0.001]).

Weaning Success

The impact of the aforementioned variables on the weaning success of the B2m^−/− deficient mice as measured by the survival rate of the pups to adulthood was examined (Fig. 3). A measure of association between the survival rate and the mating genotypes revealed a high statistical significance (P < 0.001). Mice born to a cross between heterozygous B2m^+/− females and B2m^+/− males exhibited the highest survival rate. Similar levels of significance were observed between the rate of mortality (natural death plus cannibalism) and the type of mating (P < 0.001). Pups born to B2m^−/− parents showed the poorest survival rate. In addition, the B2m^−/− mice showed a very significant disproportionate increase in postnatal mortality due to cannibalism when compared with the mice carrying the B2m gene (P < 0.001).

Fig. 3 — Weaning success is increased on a *B2m*-positive background. Weaned percentage is illustrated for all four mating crosses; *B2m*^−/− × *B2m*^−/− (38.8%), *B2m*^+/+ × *B2m*^+/+ (60.9%), *B2m*^+/+ × *B2m*^−/− (84.7%), *B2m*^−/− × *B2m*^+/+ (87.5%) and *B2m*^+/− × *B2m*^+/− (92.8%). Number of mating crosses (N) is indicated. Due to a high degree of cannibalism in the *B2m*^−/−-deficient mice, the weaned success is lower compared with the *B2m*^+/+ wild-type mice. Incidence of natural deaths and cannibalism falls for the *B2m*^+/+ × *B2m*^−/− and *B2m* × *B2m*^+/− mating crosses, and hence weaning success increases. Results are expressed as mean ± SEM. Chi-square test was used to determine differences between the groups. ***P ≤ 0.001.

Mating Frequency, Superovulation, and Estrous Cycle

Mating frequency was significantly reduced in the B2m deficient dams compared with the B2m^+/+ wild-type mice. A reduction of the percentage of mating on Night 1 to Night 4 on B2m deficient (66 ± 3, P < 0.01) versus the B2m wild-type mice (90 ± 5) was observed. I. nterestingly, the capacity of the B2m-deficient mouse strain to respond to superovulation with the hormone hCG and eCG was similar to other mouse strains (Table 2). Moreover, there was no difference in the estrous cycle analysis between B2m deficient and wild-type female mice (Fig. 4). These results suggest that the B2m^−/− mice have an intact and responding corpus luteum and therefore a normal ovulation pattern. The possibility of resorption of the entire litter as a cause of poor breeding was ruled out, since mating of a B2m^−/− female, detected by the presence of vaginal plugs, normally led to a successful pregnancy and the birth of a litter.

Table 2.

Number of ovulating mice and number of ovulated oocytes per animal from stimulated adult females and naturally cycling control females.

Female	Treatment	No. of mice that ovulated	No. of ovulated oocytes (range)^a
Natural controls	None	10/10	18.0 ± 0.8 (15–20)
B2m ^+/+	5 IU (hCG) + 5 IU (eCG)	10/10	59.0 ± 4.9 (48–77)^**
B2m ^+/−	5 IU (hCG) + 5 IU (eCG)	10/10	63.2 ± 4.8 (52–80)^**
B2m ^−/−	5 IU (hCG) + 5 IU (eCG)	10/10	61.7 ± 3.7 (50–78)^**

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^{^a}

Values are presented as mean ± SEM (n = 10).

^**

P < 0.01 versus control group analyzed by Student t-test.

Fig. 4 — Estrous cycle in vaginal fluid samples from *B2m-*deficient and wild-type female mice. Representative images of the samples from proestrus, estrus, metestrus, and diestrus (estrous cycle) stained with hematoxylin/eosin. Original magnification ×400.

Discussion

In this study we have shown that the B2m knockout mouse has an impaired breeding phenotype (IBP). The results implicate the absence of B2M, and consequently diminished expression of MHC Class I in the altered reproductive performance of this mouse strain. The female B2m^−/− mice also exhibited a high level of cannibalism towards the newborn pups, suggestive of an alteration of the maternal nurturing behavior and the mechanism that control progeny recognition by the mother. The cannibalistic behavior of the B2m^−/− mice extends observations on the relationship of offspring recognition by the mother, and communal nesting and communal nursing in mice [19].

B2M is found in the serum and body fluids, both in a free form and associated with MHC class I heavy chain. Previous studies have shown that soluble MHC Class I molecules can act as pheromones, influencing mating signals within rodent colonies [35–39]. Therefore, a possible mechanism operating in the B2m-deficient mice is the absence of secreted MHC class I products, and thus the absence of mating signals resulting in impaired breeding. This mechanism might also render the female unable to recognize the offspring as her own, leading to cannibalistic behavior. It has been postulated that MHC genes act as kin-recognition markers to increase relatedness among communal nesting partners [21, 24, 52]. Mice can recognize one another by individual characteristic body odors that reflect their genetic constitution at the MHC [22] and mothers are able to recognize syngeneic pups from other pups differing only in MHC [23]. Pup lethality, a form of cannibalism affecting female nurturing behavior, has also been reported as a result of fosB gene deficiency [53]; although in a different context, the phenotypic effect bears some similarity to the effect of the B2m deficiency. In humans, there is also data suggesting that MHC genes are linked to olfactory receptors and act as odor recognition cues in mating choices [44–49].

The homozygous B2m^−/− and heterozygous B2m^+/− females produce the same number of oocytes following superovulation as the control B2m^+/+ females, suggesting that they should produce as many offspring per mating as their wild-type counterparts. However, litter sizes are smaller indicating that a lack of B2m impairs embryo development. The B2m^−/− mice have a severely diminished expression of MHC Class I products both in the adult tissues and throughout development. A reasonable postulate is that B2M and, in turn, MHC deficiency are implicated in the poor breeding capacity of the B2m deficient mice by affecting mating, embryo development, and maternal behavior.

The IBP phenomenon can be rescued by introducing the B2m gene back into the genome of the mice. Breeding experiments in which C57BL/6 B2m^−/− transgenic mice were crossed with the C57BL/6 B2m^+/+ parental mouse strain restored the reproductive pattern of the heterozygous progeny to normality. These observations are consistent with the notion that MHC disassortative mating preferences, driven probably by pathogens, favor MHC heterozygosity [54].

The impact of variations in the maternal uterine genotype and maternal cytoplasmic contributions to the oocyte has been controlled by use of mice of identical C57BL/6 genetic background in all crosses. The only genetic variable is the presence or absence of functional B2m allele(s). In previous studies, we have shown that C57BL/6 (H2-D^b) derived MHC Class I products are synthesized at the one-cell embryo stage, arguing for a requirement of MHC in development [55]. This finding was confirmed in another mouse strain; Arcellana-Panlilio and Schultsz showed that in the CD-1 Swiss albino mice, H-2 K^q products were also expressed at all stages of preimplantation development [56]. The exact mechanism for a role of MHC in early development is still unclear. It may involve stage-specific antigen synthesis to allow differentiation and cell division, similar to the role of differentiation molecules involved in the ontogeny of lymphocytes [57]. MHC-mediated transmembrane signaling pathways, particularly in the case of H2-Q products, which have glycosidylinositolphosphate, anchored transmembrane domains [58] might also be a signal mechanism operating in mammalian embryogenesis. We have postulated that a background level of MHC Class I is required for successful mouse development and for protection against maternal large granular cells and natural killer cells (NK) [59], as it has become established that in the adult, NK effector cell recognition involves targeting cells with diminished MHC expression [60].

Conversely, it has also been shown that overexpression of MHC Class I products has a detrimental effect on development. Indeed, Jaffe and colleagues have shown that embryos overexpressing H-2D^d antigen under the control of the human beta-actin promoter, when introduced into pseudopregnant syngeneic foster females fail to develop past the mid-point of gestation; while control embryos that overexpressed an irrelevant protein developed normally [61]. The above observations suggest that a homeostatic level of MHC might be protective and influence normal development and viability early in life. It is possible that in the B2m^−/− mouse strain the lack of B2M impairs the synthesis and cell-surface expression of MHC Class I, thus altering the normal balance of MHC expression during early stages of development. B2M normally associates with the Fc receptor of the placenta [3], therefore, in the pregnant female B2m^−/− mice, the Fc receptor may have a reduced capacity to transport IgG molecules across the placenta to the developing embryo, affecting development and reducing litter size.

Taken together these results indicate that the B2m deficient mouse strain has an impaired reproductive pattern, that we have termed Impaired Breeding Phenotype (IBP). The acquisition of IBP as a result of selective genetic deficiency of B2m directly implicates the B2M protein in the reproductive cycle of mice and raises the possibility of an effect of B2M in the reproduction in humans.

Acknowledgments

We would like to thank Dr. Geoffrey Butcher (Babraham, Cambridge) and Dr. Richard D. Jurd (University of Essex, England) for reading the manuscript and for their advice and helpful suggestions.

References

1. Klein J. The natural history of the major histocompatibility complex. New York: John Wiley; 1993:233. [Google Scholar]
2. Bleicher PA, Balk SP, Hagen SJ, Blumberg RS, Flotte TJ, Terhorst C. Expression of murine CD1 on gastrointestinal epithelium. Science 1990; 250:679–682. [DOI] [PubMed] [Google Scholar]
3. Story CM, Mikulska JE, Simister NE. A major histocompatibility complex Class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med 1994; 180:2377–2381. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Simister NE, Mostov KE. An Fc receptor structurally related to MHC Class I antigens. Nature 1989; 337:184–187. [DOI] [PubMed] [Google Scholar]
5. Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, Petkova S, Avanessian L, Choi EY, Shaffer DJ, Eden PA, Anderson CL. The MHC Class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol 2003; 170:3528–3533. [DOI] [PubMed] [Google Scholar]
6. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 2003; 197:315–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL et al. A novel MHC Class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13:399–408. [DOI] [PubMed] [Google Scholar]
8. Kvist S, Levy F. Early events in the assembly of MHC class I antigens. Semin Immunol 1993; 5:105–116. [DOI] [PubMed] [Google Scholar]
9. Allen H, Fraser J, Flyer D, Calvin S, Flavell R. β₂-microglobulin is not required for cell surface expression of the murine Class I histocompatibility antigen H-2 D^b or a truncated H-2 D^b. Proc Natl Acad Sci U S A 1986; 83:7447–7451. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in beta-2-m, MHC Class I proteins, and CD8+ T cells. Science 1990; 248:1227–1229. [DOI] [PubMed] [Google Scholar]
11. Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH, Jaenisch R. Beta-2-microglobulin deficient mice lack CD4⁻ CD8⁺ cytolytic T cells. Nature 1990; 344:742–746. [DOI] [PubMed] [Google Scholar]
12. Glas R, Ohlen C, Hoglund P, Karre K. The CD8+ repertoire in β2-microglobulin deficient mice is biased towards reactivity against self-major histocompatibility Class I. J Exp Med 1994; 179:661–672. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Tarleton R, Koller B, Latour A, Postan M. Susceptibility of β₂-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature 1992; 356:338–340. [DOI] [PubMed] [Google Scholar]
14. Wang Z, Reiner SL, Hatam F, Heinzel FP, Bouvier J, Turck CW, Locksley RM. Targeted activation of CD8 cells and infection of β₂-microglobulin-deficient mice fail to confirm a primary protective role for CD8 cells in experimental Leishmaniasis. J Immunol 1993; 151:2077–2086. [PubMed] [Google Scholar]
15. Van der Heyde HC, Manning DD, Roopenian DC, Weidanz WP. Resolution of blood-stage malarial infections in CD8+ cell deficient β₂-m−/− mice. J Immunol 1993; 151:3187–3191. [PubMed] [Google Scholar]
16. Fiette L. Theiler's virus infection of β₂-microglobulin-deficient mice. J Virology 1993; 67:589–592. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Lavi E, Das Sarma J, Weiss SR. Cellular reservoirs for coronavirus infection of the brain in beta(2)-microglobulin knockout mice. Pathobiology 1999; 67:75–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Major AS, Cuff CF. Enhanced mucosal and systemic immune responses to intestinal reovirus infection in beta-2-microglobulin-deficient mice. J Virology 1997; 71:5782–5789. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Rothenberg BE, Voland JR. β₂-m Knockout mice develop parenchymal iron overload: a putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc Natl Acad Sci U S A 1996; 93:1529–1534. [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Bard J, Yamazaki K, Curran M, Boyse EA, Beauchamp GK. Effect of β₂-m gene disruption on MHC-determined odortypes. Immunogenetics 2000; 51:514–518. [DOI] [PubMed] [Google Scholar]
21. Brown JL, Eklund A. Kin recognition and the major histocompatibility complex—an integrative review. American Naturalist 1994; 143:435–461. [Google Scholar]
22. Beauchamp GK, Curran M, Yamazaki K. MHC-mediated fetal odourtypes expressed by pregnant females influence male associative behaviour. Animal Behaviour 2000; 60:289–295. [DOI] [PubMed] [Google Scholar]
23. Yamazaki K, Beauchamp GK, Curran M, Bard J, Boyse EA. Parent-progeny recognition as a function of MHC odortype identity. Proc Natl Acad Sci U S A 2000; 97:10500–10502. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Manning CJ, Wakeland EK, Potts WK. Communal nesting patterns in mice implicate MHC genes in kin recognition. Nature 1992; 360:581–583. [DOI] [PubMed] [Google Scholar]
25. Yamazaki K, Beauchamp GK, Bard J, Boyse EA. Discrimination of odour differences in MHC-deficient mice. Behavior Genetics 1998; 28:486. [Google Scholar]
26. Yamazaki K, Singer A, Beauchamp GK. Origin, functions and chemistry of H-2 regulated odorants. Genetica 1998; 104:235–240. [DOI] [PubMed] [Google Scholar]
27. Penn D, Potts W. How do major histocompatibility complex genes influence odour and mating preferences? Advances Immunol 1998; 69:411–436. [DOI] [PubMed] [Google Scholar]
28. Yamazaki K, Beauchamp GK, Shen FW, Bard J, Boyse EA. Discrimination of odortypes determined by the major histocompatibility complex among outbred mice. Proc Natl Acad Sci U S A 1994; 91:3735–3738. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Beauchamp GK, Yamazaki K, Curran M, Bard J, Boyse EA. Fetal H-2 odortypes are evident in the urine of pregnant female mice. Immunogenetics 1994; 39:109–113. [DOI] [PubMed] [Google Scholar]
30. Beauchamp GK, Yamazaki K, Wysocki CJ, Slotnick BM, Thomas L, Boyse EA. Chemosensory recognition of mouse major histocompatibility types by another species. Proc Natl Acad Sci U S A 1985; 82:4186–4188. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Brown RE, Singh PB, Roser B. The major histocompatibility complex and the chemosensory recognition of individuality in rats. Physiology and Behavior 1987; 40:65–73. [DOI] [PubMed] [Google Scholar]
32. Potts WK, Manning CJ, Wakeland EK. Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature 1991; 352:619–621. [DOI] [PubMed] [Google Scholar]
33. Singer AG, Beauchamp GK, Yamazaki K. Volatile signals of the major histocompatibility complex in male mouse urine. Proc Natl Acad Sci U S A 1997; 94:2210–2214. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Janssen E, Gohlen B, Behrens D, Richter K, Zavazava N. Allogeneic recombinant soluble MHC class I molecules modify urinary odor cues in rats. Physiology and Behavior 2001; 72:107–114. [DOI] [PubMed] [Google Scholar]
35. Singh PB, Brown RE, Roser B. MHC antigens in urine as olfactory recognition cues. Nature 1987; 327:161–164. [DOI] [PubMed] [Google Scholar]
36. Brown JL, Eklund A. Kin recognition and the major histocompatibility complex: an integrative review. American Naturalist 1994; 143:435–461. [Google Scholar]
37. Beauchamp GK, Yamazaki K, Curran M, Bard J, Boyse EA. Fetal odortypes are evident in the urine of pregnant female mice. Immunogenetics 1994; 39:109–113. [DOI] [PubMed] [Google Scholar]
38. Yamazaki K, Beauchamp GK. Olfactory individuality. Chemical Senses 2005; 30:142–143. [DOI] [PubMed] [Google Scholar]
39. Yamaguchi M, Yamazaki K, Beauchamp GK, Bard J, Thomas L, Boyse EA. Distinctive urinary odors governed by the major histocompatibility locus of the mouse. Proc Natl Acad Sci U S A 1981; 78:5817–5820. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Yamazaki K, Beauchamp GK, Shen FW, Bard J, Boyse EA. A distinctive change in odortype determined by H-2D-1 mutation. Immunogenetics 1991; 34:129–131. [DOI] [PubMed] [Google Scholar]
41. Yamazaki K, Beauchamp GK, Imai Y, Bard J, Phelan SP, Thomas L, Boyse EA. Odortypes determined by the major histocompatibility complex in germ-free mice. Proc Natl Acad Sci U S A 1990; 87:8413–8416. [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Yamazaki K, Beauchamp GK, Bard J, Thomas L, Boyse EA. Chemosensory recognition of phenotypes determined by the tla and H-2K regions of chromosome-17 of the mouse. Proc Natl Acad Sci U S A 1982; 79:7828–7831. [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Yamazaki K, Beauchamp GK, Imai Y, Bard J, Boyse EA. Expression of urinary H-2 odortypes by infant mice. Proc Natl Acad Sci U S A 1992; 89:2756–2758. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Fan WF, Liu YC, Parimoo S, Weissman SM. Olfactory receptor-like genes are located in the human major histocompatibility complex. Genomics 1995; 27:119–123. [DOI] [PubMed] [Google Scholar]
45. Beauchamp GK, Katahira K, Yamazaki K, Mennella JA, Bard J, Boyse EA. Evidence suggesting that the odortypes of pregnant-women are a compound of maternal and fetal odortypes. Proc Natl Acad Sci U S A 1995; 92:2617–2621. [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Ehlers A, Beck S, Forbes SA, Trowsdale J, Volz A, Younger R, Ziegler A. MHC-linked olfactory receptor loci exhibit polymorphism and contribute to extended HLA/OR-haplotypes. Genome Research 2000; 10:1968–1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Hedrick PW, Black FL. HLA and mate selection: no evidence in south Amerindians. Amer J Human Genet 1997; 61:505–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S. HLA and mate choice in humans. Amer J Human Genet 1997; 61:497–504. [DOI] [PMC free article] [PubMed] [Google Scholar]
49. Jacob S, McClintock MK, Zelano B, Ober C. Paternally inherited HLA alleles are associated with women's choice of male odor. Nat Genet 2002; 30:175–179. [DOI] [PubMed] [Google Scholar]
50. Cooper JC, Fernandez N, Dealtry GB. A highly sensitive RT-PCR system for analysing gene expression in embryos and single cells. Immunology 1994; 83:1–51.7821954 [Google Scholar]
51. Dealtry GB, Cooper JC, Sprinks MT, Sellens MH, Fernandez N. Expression and assembly of MHC Class I products and associated molecules during pre-implantation development. Genet Res 1995; 65:3–10. [Google Scholar]
52. Manning CJ, Dewsbury DA, Wakeland EK, Potts WK. Communal nesting and communal nursing in house mice, mus musculus domesticus. Animal Behaviour 1995; 50:741–751. [Google Scholar]
53. Brown JR, Ye H, Bronson RT, Dikkes P, Greenberg ME. A defect in nurturing in mice lacking the immediate early gene fosB. Cell 1996; 86:297–309. [DOI] [PubMed] [Google Scholar]
54. Potts WK, Manning CJ, Wakeland EK. The role of infectious disease, inbreeding and mating preferences in maintaining MHC genetic diversity—an experimental test. Philosophical Transactions of the Royal Society of London Series B—Biological Sciences 1994; 346:369–378. [DOI] [PubMed] [Google Scholar]
55. Sprinks MT, Sellens MH, Dealtry GB, Fernandez N. Preimplantation mouse embryos express MHC class I genes before the first cleavage division. Immunogenetics 1993; 38:35–40. [DOI] [PubMed] [Google Scholar]
56. Arcellana-Panlilio MY, Shultz GA. Temporal and spatial expression of major histocompatibility complex Class I H-2 K in the early mouse embryo. Biol Reprod 1994; 51:169–183. [DOI] [PubMed] [Google Scholar]
57. Fernandez N, Cooper J, Sprinks M, AbdElrahman M, Fiszer D, Kurpisz M, Dealtry G. A critical review of the role of the major histocompatibility complex in fertilization, preimplantation development and feto-maternal interactions. Human Reproduction Update 1999; 5:234–248. [DOI] [PubMed] [Google Scholar]
58. Stroynowski I, Soloski M, Low MG, Hood L. A single gene encodes soluble and membrane-bound forms of the major histocompatibility Qa-2 antigen: anchoring of the product by a phospholipid tail. Cell 1987; 50:759–768. [DOI] [PubMed] [Google Scholar]
59. Fernandez N, Sprinks MT, Cooper JC, Dealtry GB, Sellens MH, Reyes-Engel A, Kurpisz M. Embryonic development and the Major Histocompatibility Complex. Kurpisz M, Fernandez N. Human Reproductive Immunology. Oxford: Bios Scientific Publications; 1995:185. [Google Scholar]
60. Bix M, Liao NS, Ziljstra M, Loring J, Jaenisch R, Raulet D. Rejection of Class I MHC deficient hemopoietic cells by irradiated MHC-matched mice. Nature 1991; 349:329–331. [DOI] [PubMed] [Google Scholar]
61. Jaffe L, Robertson EJ, Bikoff E. Distinct patterns of expression of MHC class I and β₂ microglobulin transcripts at early stages of mouse development. J Immunol 1991; 147:2740–2750. [PubMed] [Google Scholar]

[R1] 1. Klein J. The natural history of the major histocompatibility complex. New York: John Wiley; 1993:233. [Google Scholar]

[R2] 2. Bleicher PA, Balk SP, Hagen SJ, Blumberg RS, Flotte TJ, Terhorst C. Expression of murine CD1 on gastrointestinal epithelium. Science 1990; 250:679–682. [DOI] [PubMed] [Google Scholar]

[R3] 3. Story CM, Mikulska JE, Simister NE. A major histocompatibility complex Class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med 1994; 180:2377–2381. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] 4. Simister NE, Mostov KE. An Fc receptor structurally related to MHC Class I antigens. Nature 1989; 337:184–187. [DOI] [PubMed] [Google Scholar]

[R5] 5. Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, Petkova S, Avanessian L, Choi EY, Shaffer DJ, Eden PA, Anderson CL. The MHC Class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol 2003; 170:3528–3533. [DOI] [PubMed] [Google Scholar]

[R6] 6. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 2003; 197:315–322. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL et al. A novel MHC Class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13:399–408. [DOI] [PubMed] [Google Scholar]

[R8] 8. Kvist S, Levy F. Early events in the assembly of MHC class I antigens. Semin Immunol 1993; 5:105–116. [DOI] [PubMed] [Google Scholar]

[R9] 9. Allen H, Fraser J, Flyer D, Calvin S, Flavell R. β₂-microglobulin is not required for cell surface expression of the murine Class I histocompatibility antigen H-2 D^b or a truncated H-2 D^b. Proc Natl Acad Sci U S A 1986; 83:7447–7451. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] 10. Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in beta-2-m, MHC Class I proteins, and CD8+ T cells. Science 1990; 248:1227–1229. [DOI] [PubMed] [Google Scholar]

[R11] 11. Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH, Jaenisch R. Beta-2-microglobulin deficient mice lack CD4⁻ CD8⁺ cytolytic T cells. Nature 1990; 344:742–746. [DOI] [PubMed] [Google Scholar]

[R12] 12. Glas R, Ohlen C, Hoglund P, Karre K. The CD8+ repertoire in β2-microglobulin deficient mice is biased towards reactivity against self-major histocompatibility Class I. J Exp Med 1994; 179:661–672. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] 13. Tarleton R, Koller B, Latour A, Postan M. Susceptibility of β₂-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature 1992; 356:338–340. [DOI] [PubMed] [Google Scholar]

[R14] 14. Wang Z, Reiner SL, Hatam F, Heinzel FP, Bouvier J, Turck CW, Locksley RM. Targeted activation of CD8 cells and infection of β₂-microglobulin-deficient mice fail to confirm a primary protective role for CD8 cells in experimental Leishmaniasis. J Immunol 1993; 151:2077–2086. [PubMed] [Google Scholar]

[R15] 15. Van der Heyde HC, Manning DD, Roopenian DC, Weidanz WP. Resolution of blood-stage malarial infections in CD8+ cell deficient β₂-m−/− mice. J Immunol 1993; 151:3187–3191. [PubMed] [Google Scholar]

[R16] 16. Fiette L. Theiler's virus infection of β₂-microglobulin-deficient mice. J Virology 1993; 67:589–592. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R17] 17. Lavi E, Das Sarma J, Weiss SR. Cellular reservoirs for coronavirus infection of the brain in beta(2)-microglobulin knockout mice. Pathobiology 1999; 67:75–83. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] 18. Major AS, Cuff CF. Enhanced mucosal and systemic immune responses to intestinal reovirus infection in beta-2-microglobulin-deficient mice. J Virology 1997; 71:5782–5789. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19. Rothenberg BE, Voland JR. β₂-m Knockout mice develop parenchymal iron overload: a putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc Natl Acad Sci U S A 1996; 93:1529–1534. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20. Bard J, Yamazaki K, Curran M, Boyse EA, Beauchamp GK. Effect of β₂-m gene disruption on MHC-determined odortypes. Immunogenetics 2000; 51:514–518. [DOI] [PubMed] [Google Scholar]

[R21] 21. Brown JL, Eklund A. Kin recognition and the major histocompatibility complex—an integrative review. American Naturalist 1994; 143:435–461. [Google Scholar]

[R22] 22. Beauchamp GK, Curran M, Yamazaki K. MHC-mediated fetal odourtypes expressed by pregnant females influence male associative behaviour. Animal Behaviour 2000; 60:289–295. [DOI] [PubMed] [Google Scholar]

[R23] 23. Yamazaki K, Beauchamp GK, Curran M, Bard J, Boyse EA. Parent-progeny recognition as a function of MHC odortype identity. Proc Natl Acad Sci U S A 2000; 97:10500–10502. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R24] 24. Manning CJ, Wakeland EK, Potts WK. Communal nesting patterns in mice implicate MHC genes in kin recognition. Nature 1992; 360:581–583. [DOI] [PubMed] [Google Scholar]

[R25] 25. Yamazaki K, Beauchamp GK, Bard J, Boyse EA. Discrimination of odour differences in MHC-deficient mice. Behavior Genetics 1998; 28:486. [Google Scholar]

[R26] 26. Yamazaki K, Singer A, Beauchamp GK. Origin, functions and chemistry of H-2 regulated odorants. Genetica 1998; 104:235–240. [DOI] [PubMed] [Google Scholar]

[R27] 27. Penn D, Potts W. How do major histocompatibility complex genes influence odour and mating preferences? Advances Immunol 1998; 69:411–436. [DOI] [PubMed] [Google Scholar]

[R28] 28. Yamazaki K, Beauchamp GK, Shen FW, Bard J, Boyse EA. Discrimination of odortypes determined by the major histocompatibility complex among outbred mice. Proc Natl Acad Sci U S A 1994; 91:3735–3738. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] 29. Beauchamp GK, Yamazaki K, Curran M, Bard J, Boyse EA. Fetal H-2 odortypes are evident in the urine of pregnant female mice. Immunogenetics 1994; 39:109–113. [DOI] [PubMed] [Google Scholar]

[R30] 30. Beauchamp GK, Yamazaki K, Wysocki CJ, Slotnick BM, Thomas L, Boyse EA. Chemosensory recognition of mouse major histocompatibility types by another species. Proc Natl Acad Sci U S A 1985; 82:4186–4188. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] 31. Brown RE, Singh PB, Roser B. The major histocompatibility complex and the chemosensory recognition of individuality in rats. Physiology and Behavior 1987; 40:65–73. [DOI] [PubMed] [Google Scholar]

[R32] 32. Potts WK, Manning CJ, Wakeland EK. Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature 1991; 352:619–621. [DOI] [PubMed] [Google Scholar]

[R33] 33. Singer AG, Beauchamp GK, Yamazaki K. Volatile signals of the major histocompatibility complex in male mouse urine. Proc Natl Acad Sci U S A 1997; 94:2210–2214. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R34] 34. Janssen E, Gohlen B, Behrens D, Richter K, Zavazava N. Allogeneic recombinant soluble MHC class I molecules modify urinary odor cues in rats. Physiology and Behavior 2001; 72:107–114. [DOI] [PubMed] [Google Scholar]

[R35] 35. Singh PB, Brown RE, Roser B. MHC antigens in urine as olfactory recognition cues. Nature 1987; 327:161–164. [DOI] [PubMed] [Google Scholar]

[R36] 36. Brown JL, Eklund A. Kin recognition and the major histocompatibility complex: an integrative review. American Naturalist 1994; 143:435–461. [Google Scholar]

[R37] 37. Beauchamp GK, Yamazaki K, Curran M, Bard J, Boyse EA. Fetal odortypes are evident in the urine of pregnant female mice. Immunogenetics 1994; 39:109–113. [DOI] [PubMed] [Google Scholar]

[R38] 38. Yamazaki K, Beauchamp GK. Olfactory individuality. Chemical Senses 2005; 30:142–143. [DOI] [PubMed] [Google Scholar]

[R39] 39. Yamaguchi M, Yamazaki K, Beauchamp GK, Bard J, Thomas L, Boyse EA. Distinctive urinary odors governed by the major histocompatibility locus of the mouse. Proc Natl Acad Sci U S A 1981; 78:5817–5820. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] 40. Yamazaki K, Beauchamp GK, Shen FW, Bard J, Boyse EA. A distinctive change in odortype determined by H-2D-1 mutation. Immunogenetics 1991; 34:129–131. [DOI] [PubMed] [Google Scholar]

[R41] 41. Yamazaki K, Beauchamp GK, Imai Y, Bard J, Phelan SP, Thomas L, Boyse EA. Odortypes determined by the major histocompatibility complex in germ-free mice. Proc Natl Acad Sci U S A 1990; 87:8413–8416. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R42] 42. Yamazaki K, Beauchamp GK, Bard J, Thomas L, Boyse EA. Chemosensory recognition of phenotypes determined by the tla and H-2K regions of chromosome-17 of the mouse. Proc Natl Acad Sci U S A 1982; 79:7828–7831. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R43] 43. Yamazaki K, Beauchamp GK, Imai Y, Bard J, Boyse EA. Expression of urinary H-2 odortypes by infant mice. Proc Natl Acad Sci U S A 1992; 89:2756–2758. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R44] 44. Fan WF, Liu YC, Parimoo S, Weissman SM. Olfactory receptor-like genes are located in the human major histocompatibility complex. Genomics 1995; 27:119–123. [DOI] [PubMed] [Google Scholar]

[R45] 45. Beauchamp GK, Katahira K, Yamazaki K, Mennella JA, Bard J, Boyse EA. Evidence suggesting that the odortypes of pregnant-women are a compound of maternal and fetal odortypes. Proc Natl Acad Sci U S A 1995; 92:2617–2621. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R46] 46. Ehlers A, Beck S, Forbes SA, Trowsdale J, Volz A, Younger R, Ziegler A. MHC-linked olfactory receptor loci exhibit polymorphism and contribute to extended HLA/OR-haplotypes. Genome Research 2000; 10:1968–1978. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R47] 47. Hedrick PW, Black FL. HLA and mate selection: no evidence in south Amerindians. Amer J Human Genet 1997; 61:505–511. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R48] 48. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S. HLA and mate choice in humans. Amer J Human Genet 1997; 61:497–504. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R49] 49. Jacob S, McClintock MK, Zelano B, Ober C. Paternally inherited HLA alleles are associated with women's choice of male odor. Nat Genet 2002; 30:175–179. [DOI] [PubMed] [Google Scholar]

[R50] 50. Cooper JC, Fernandez N, Dealtry GB. A highly sensitive RT-PCR system for analysing gene expression in embryos and single cells. Immunology 1994; 83:1–51.7821954 [Google Scholar]

[R51] 51. Dealtry GB, Cooper JC, Sprinks MT, Sellens MH, Fernandez N. Expression and assembly of MHC Class I products and associated molecules during pre-implantation development. Genet Res 1995; 65:3–10. [Google Scholar]

[R52] 52. Manning CJ, Dewsbury DA, Wakeland EK, Potts WK. Communal nesting and communal nursing in house mice, mus musculus domesticus. Animal Behaviour 1995; 50:741–751. [Google Scholar]

[R53] 53. Brown JR, Ye H, Bronson RT, Dikkes P, Greenberg ME. A defect in nurturing in mice lacking the immediate early gene fosB. Cell 1996; 86:297–309. [DOI] [PubMed] [Google Scholar]

[R54] 54. Potts WK, Manning CJ, Wakeland EK. The role of infectious disease, inbreeding and mating preferences in maintaining MHC genetic diversity—an experimental test. Philosophical Transactions of the Royal Society of London Series B—Biological Sciences 1994; 346:369–378. [DOI] [PubMed] [Google Scholar]

[R55] 55. Sprinks MT, Sellens MH, Dealtry GB, Fernandez N. Preimplantation mouse embryos express MHC class I genes before the first cleavage division. Immunogenetics 1993; 38:35–40. [DOI] [PubMed] [Google Scholar]

[R56] 56. Arcellana-Panlilio MY, Shultz GA. Temporal and spatial expression of major histocompatibility complex Class I H-2 K in the early mouse embryo. Biol Reprod 1994; 51:169–183. [DOI] [PubMed] [Google Scholar]

[R57] 57. Fernandez N, Cooper J, Sprinks M, AbdElrahman M, Fiszer D, Kurpisz M, Dealtry G. A critical review of the role of the major histocompatibility complex in fertilization, preimplantation development and feto-maternal interactions. Human Reproduction Update 1999; 5:234–248. [DOI] [PubMed] [Google Scholar]

[R58] 58. Stroynowski I, Soloski M, Low MG, Hood L. A single gene encodes soluble and membrane-bound forms of the major histocompatibility Qa-2 antigen: anchoring of the product by a phospholipid tail. Cell 1987; 50:759–768. [DOI] [PubMed] [Google Scholar]

[R59] 59. Fernandez N, Sprinks MT, Cooper JC, Dealtry GB, Sellens MH, Reyes-Engel A, Kurpisz M. Embryonic development and the Major Histocompatibility Complex. Kurpisz M, Fernandez N. Human Reproductive Immunology. Oxford: Bios Scientific Publications; 1995:185. [Google Scholar]

[R60] 60. Bix M, Liao NS, Ziljstra M, Loring J, Jaenisch R, Raulet D. Rejection of Class I MHC deficient hemopoietic cells by irradiated MHC-matched mice. Nature 1991; 349:329–331. [DOI] [PubMed] [Google Scholar]

[R61] 61. Jaffe L, Robertson EJ, Bikoff E. Distinct patterns of expression of MHC class I and β₂ microglobulin transcripts at early stages of mouse development. J Immunol 1991; 147:2740–2750. [PubMed] [Google Scholar]

PERMALINK

An Impaired Breeding Phenotype in Mice with a Genetic Deletion of Beta-2 Microglobulin and Diminished MHC Class I Expression: Role in Reproductive Fitness^¹

Joanne C Cooper

Gillian B Dealtry

Mohamed Abdelrahman Ahmed

Petra C Arck

Burghard F Klapp

Sandra M Blois

Nelson Fernández

Abstract

Introduction