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Endocrinology Vol. 145, No. 10 4447-4451
Copyright © 2004 by The Endocrine Society

Chromosomes 6 and 13 Harbor Genes that Regulate Pubertal Timing in Mouse Chromosome Substitution Strains

Thomas D. Krewson, Pamela J. Supelak, Annie E. Hill, Jonathan B. Singer, Eric S. Lander, Joseph H. Nadeau and Mark R. Palmert

Division of Pediatric Endocrinology and Metabolism (T.D.K., P.J.S., M.R.P.), Rainbow Babies and Children’s Hospital, and Center for Human Genetics (J.H.N.), University Hospitals of Cleveland, and Departments of Pediatrics (T.D.K., P.J.S., M.R.P.) and Genetics (A.E.H., J.H.N., M.R.P.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; The Broad Institute of MIT and Harvard (J.B.S., E.S.L.), Cambridge, Massachusetts 02141; The Whitehead Institute for Biomedical Research (J.B.S., E.S.L.), Cambridge, Massachusetts 02142; and Massachusetts Institute of Technology (E.S.L.), Cambridge, Massachusetts 02139

Address all correspondence and requests for reprints to: Mark R. Palmert, M.D., Ph.D, Division of Pediatric Endocrinology and Metabolism, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: mark.palmert{at}case.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Variation in the onset of puberty among inbred strains of mice suggests that quantitative trait loci (QTLs) affect neurological and hormonal aspects of sexual maturation. Taking a novel approach toward identifying factors that regulate the hypothalamic-pituitary-gonadal (HPG) axis, we evaluated pubertal timing [as assessed by vaginal opening (VO)] in two inbred strains of mice, A/J and C57BL/6J (B6), and in a panel of chromosome substitution strains (CSSs) generated from A/J and B6 mice. In each CSS, a single chromosome from A/J has been substituted in a homozygous fashion for the corresponding chromosome in B6, partitioning the A/J genome into 22 strains with a common host (B6) background. VO occurred significantly earlier in A/J compared with B6 mice. Although the majority of the CSSs assessed had a timing of VO that was similar to the progenitor B6 strain, CSSs for chromosomes 6 and 13 each displayed significantly earlier time of VO than B6 mice. F1 (B6 x CSS) mice for chromosomes 6 and 13 displayed phenotypes that were intermediate between the CSS and B6 strains, suggesting that the trait was inherited in a codominant manner. These findings demonstrate that chromosomes 6 and 13 harbor QTLs that control the timing of VO. Identification of the responsible genes may reveal factors that regulate the maturation of the HPG axis and determine the timing of puberty.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IDENTIFYING FACTORS THAT regulate the maturation of the hypothalamic-pituitary-gonadal (HPG) axis is important to our understanding of a pubertal development and of pathophysiology of reproductive endocrine disorders, such as precocious and delayed puberty and hypogonadotropic hypogonadism. It is increasingly recognized that genetic factors modulate the timing of puberty (1, 2, 3), but little is known about the genes that mediate these effects. Data correlating the timing of puberty between parents and children, among population groups, and between monozygotic twins indicate that up to 50–80% of the variance in pubertal timing within the general population is genetically determined (reviewed in Refs.1, 2, 3). Discovery of the genes that affect the timing of puberty would provide an opportunity to identify factors that coordinate the developmental and functional aspects of the HPG axis in humans.

Although not all genes and pathways are shared between mice and humans, a growing number of examples demonstrate that the investigation of variation among inbred mouse strains is a powerful tool for the identification of genetic modulators of human traits and diseases (4, 5, 6). Previous work has shown that the timing of puberty [as assessed by vaginal opening (VO)] varies among inbred strains of mice (7, 8). These data indicate that this trait is genetically controlled and raise the possibility that these strain differences could be used to identify genes that modulate the onset of puberty. Such an approach has the advantage of not being biased toward known biological pathways and, therefore, has the potential to lead to the identification of novel factors. Any genes and pathways identified would become candidates for regulating the HPG axis in humans.

Characterization of a full panel of chromosome substitution strains (CSSs) represents a new strategy for identifying genes that regulate complex traits (9, 10). Here we report that the timing of VO differs between two inbred strains of mice (C57BL/6J and A/J) and the use of CSSs generated from these two strains to identify chromosomes that harbor quantitative trait loci (QTLs) that regulate pubertal timing.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and housing
All animals used in this study were cared for according to a Case Western Reserve University approved protocol and Institutional Animal Care and Use Committee guidelines. Male and female mice were obtained for inbred strains C57BL/6J (JR000664) and A/J (JR000646) from The Jackson Laboratory (Bar Harbor, ME). Chromosome substitution strains were previously generated for the C57BL/6J (referred to as B6) and A/J strains (9). In the complete panel of these animals, a single chromosome from the donor strain (A/J) was substituted in a homozygous fashion for the corresponding chromosome in the host strain (B6), neatly partitioning the genome into 22 strains (19 autosomes, two sex chromosomes, and the mitochondria) that reside on a defined and uniform genetic background. CSSs for each of the 19 autosomes (referred to as B6-1A, B6-2A, B6-3A, etc.) and for the X chromosome (B6-XA) were used as breeders for this study.

All mice used in this study were housed in standard polysulfone microisolator cages with corncob bedding and provided access to chow [Prolab Isopro RMH 3000 (PMI Nutrition International, LLC; Brentwood MO)] and sterile water ad libitum. Animals were maintained on a 12-h light, 12-h dark schedule (lights on at 0600 h) at a mean ambient temperature of 72 F. For breeding, individual males were placed in a cage with two to three females for approximately 14–18 d. To minimize the exposure of female pups to male pheromonal and hormonal signals, each female breeder was then isolated in a clean cage containing a sterile cotton nestlet for the remainder of the pregnancy. Breeders were monitored daily, 7 d/wk, between 0800 and 1300 h for birth, and the date of birth was designated as the day pups were observed. Pups were weaned between the ages of 20–21 d, and males and females were then housed separately. No more than five female pups were housed per cage to ensure that access to food and water was unfettered. Assessment of multiple litters and periodic cage rotations were used to minimize the impact of environmental differences among strains. To ensure that no environmental or methodological changes occurred during the CSS survey that might have systematically affected our results, the progenitor strains (B6 and A/J) were periodically rebred, and the timing of VO was reassessed throughout the course of the experimentation to verify that the originally observed changes in VO were persistent.

Assessment of pubertal onset and analysis of chromosome substitution strains
Beginning on the day of weaning, female mice were examined daily, 7 d/wk, between 0800 and 1300 h, and the date of VO and concurrent body weight were recorded. The initial characterization of each strain was based on a minimum of three pups per strain. Any strain showing evidence of either altered timing or altered variability compared with the B6 progenitor strain underwent additional matings for replication and further statistical analysis. To assess whether the earlier VO was associated with advancement of other pubertal characteristics, vaginal lavages and microscopic characterization of epithelia were performed daily on a subset of A/J and B6 mice beginning on the day of VO and continuing through a full estrous cycle (11).

Data analysis
Two-tailed, nonparametric tests for independent variables (Mann-Whitney U Tests) were used for comparisons of time of VO and body weight. ANOVA was used for comparison of litter sizes. P values for the comparison of the time of VO between each CSS strain and the B6 progenitor strain were corrected for multiple hypothesis testing using a factor of 20 because 20 strains (19 autosomes, the X chromosome) were assessed during this study. Analyses were performed using the Complete Statistical System: Statistica from StatSoft, Inc. (Tulsa, OK). Significance was attributed to P < 0.05 for all tests except for the analysis of the timing of VO among the 20 CSSs (Table 1Go), where significance was attributed to P < 0.0025 (0.05/20 tests).


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  		TABLE 1. Timing of VO

 

   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
VO occurred significantly earlier in A/J compared with B6 mice (Table 1Go and Fig. 1Go). This effect was not simply because A/J mice grew more quickly and reached a similar weight as B6 at a younger age. Rather, A/J mice had significantly lower body weights than the B6 animals at the time of VO (P < 0.000001) (Table 1Go). There was also no evidence for differences in litter sizes between the two strains (mean of 7.6 ± 1.7, range 5–12 for A/J; mean of 7.6 ± 2.8, range of 5–10 for B6; P = 0.95). Our analyses were designed to investigate the genetic regulation of the timing of VO, but estrous cycles were assessed in a subset of the AJ and B6 animals. Although the A/J animals were younger than the B6 mice at VO, the two strains had similar time from VO to first estrus, providing further evidence that the A/J animals were maturing earlier than the B6 animals.



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  		FIG. 1. Comparison of the timing of VO. The cumulative percent of animals with VO is displayed. The two progenitor strains (A/J and B6) as well as each of the chromosome substitution strains are shown. CSSs with statistically significant differences in the timing of VO compared with B6 mice are shown in black; all other CSSs are shown in gray to provide a measure of the similarity of these strains with the B6 animals.

 
To determine the chromosomal locations of genes that contribute to this difference in pubertal timing, we surveyed VO among 20 CSSs. The initial screen of the CSSs was performed using a minimum of three pups per strain and revealed that the majority of the CSSs had a timing of VO that was similar to the progenitor B6 strain (Table 1Go and Fig. 1Go). However, two strains emerged as having reproducible and robust differences compared with the B6 mice (Table 1Go and Fig. 1Go). B6-13A had significantly earlier time of VO, with an average age approaching that seen in the A/J mice. B6-6A also had significantly earlier time of VO, but not as early as that seen in the A/J mice. Similar to the A/J animals, the B6-13A mice had significantly lower body weights than the B6 animals at the time of VO (P < 0.000001) (Table 1Go). Among all the CSSs, individual litter sizes ranged from two to 11 mice; the mean litter sizes for each strain ranged from a minimum of 5.0 in B6-14A to a maximum of 8.7 in B6-2A, with an overall mean of 6.6 ± 2.0 animals; ANOVA revealed no evidence of significant differences among the individual strains (P = 0.88). For each CSS, the number of litters and number of females assessed is displayed in Table 1Go.

To test for parent-of-origin effects (such as strain-dependent differences in nurturing or imprinting) F1 hybrid mice were generated for the B6-6A and B6-13A strains. In these experiments, the CSS mice were mated with B6 animals in reciprocal [(B6-iA x B6 ) and (B6 x B6-iA)] crosses. No substantial parent-of-origin effects were observed for either CSS (Table 2Go). Because the F1 mice are heterosomic for the B6 and A/J chromosome being evaluated, these mice also permit assessment of modes of inheritance. Both the B6-6A x B6 mice and the B6-13A x B6 mice displayed intermediate phenotypes (Table 2Go and Fig. 2Go), with VO occurring earlier than in the B6 mice (P = 0.004 for B6-6A and P = 0.0003 for B6-13A) but not as early as in the mice that are homozygous for A/J chromosome 6 (P = 0.01) or the mice that are homozygous for A/J chromosome 13 (P = 0.02). These intermediate phenotypes indicate that the locus (or loci) on each chromosome is sensitive to gene dosage effects as measured by the number of copies of A/J or B6 derived alleles (with each allele being present in zero, one, or two copies, depending on the strain). Alternatively, two or more loci with dominant and recessive effects may be involved.


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  		TABLE 2. Timing of VO in B6 x CSS F1 generations

 


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  		FIG. 2. Comparison of the timing of VO in F1 mice. The cumulative percent of animals with VO is displayed. Data from the progenitor B6 strain are included to facilitate comparison of time of VO among the B6, the homozygous CSS, and F1 mice. Top, Data for B6-6A mice. Bottom, Data for B6-13A mice.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We assessed VO among CSSs as a means of performing a genome-wide scan for genes that regulate pubertal timing. Our findings demonstrate that chromosomes 6 and 13 harbor variants that substantially affect the timing of VO in mice and lay the foundation for studies designed to map the QTLs and establish the identities of the responsible genes.

It is possible that other chromosomes contain QTLs that affect the timing of VO. Our study was designed to detect genes that exert large effects on the timing of VO and used a small number of mice to screen each strain for differences in the timing of VO. The study was not designed to detect chromosome substitutions that resulted in subtle effects. In addition, a CSS survey can only detect the effects of genes that differ between the progenitor strains, and because each CSS has a single substituted A/J chromosome, the technique is not ideally suited to detect A/J alleles whose effects depend on other A/J alleles on other chromosomes. These considerations are relevant because on average the A/J mice experience VO 5.6 d earlier than B6 mice, whereas the B6-6A mice open an average of 2.9 d earlier and the B6-13A mice open an average of 4.4 d earlier. Thus, on average, the combination of the alterations in the time of VO exhibited by the B6-6A and B6-13A CSS predicts VO at an earlier age than is observed in the progenitor A/J strain, raising the possibility that other loci on other chromosomes delay the timing of VO or that the effects exerted by the loci on chromosomes 6 and 13 are not fully additive. The possibility of other QTLs is also raised by strains B6-5A, B6-11A, and B6-12A that displayed substantial variation in the timing of VO (see Table 1Go), perhaps secondary to QTLs on these chromosomes that exert subtle effects, with variable penetrance, on the timing of puberty.

A reliable and rapid method is needed to characterize the timing of puberty among many strains of mice. The timing of VO is known to be estrogen dependent and is a well-accepted method of studying pubertal timing in rodents. It has been used in studies of N-methyl-D-aspartate analogs (12, 13), the {gamma}-aminobutyric acid system (14, 15), leptin administration (16, 17), and cranial irradiation (18), as well as a host of other mediators. In experiments designed to alter pubertal timing, VO usually correlates well with other markers of pubertal development in mice, such as estradiol levels, uterine weight, ovarian weight, and age at first ovulation (17, 19, 20). Many of these studies provide evidence that VO is linked to central pubertal activation because perturbations of gonadotropin secretion result in alterations in the timing of VO. Moreover, GnRH pulse frequencies have been shown to increase during the pubertal transition, as assessed by VO, in female rats (21).

Although known to correlate, it is unlikely that the different markers of puberty in mice (VO, organ weights, time to first estrus and ovulation) will change in parallel in all instances. Some differential responses are probable because each characteristic is likely regulated by common and independent factors. For example, factors that affect GnRH secretion may influence all characteristics, but factors that control follicle maturation may have effects that are limited to estrous cycling and ovulation. Indeed, previous genetic analyses indicate that different genetic influences may regulate the timing of VO, first vaginal cornification, and the onset of cyclicity (8) and that the determinants of cycle frequency may differ from those of cycle length (11). Thus, monitoring VO is unlikely to characterize fully the reproductive endocrine axis. On the other hand, the available data strongly suggest that genes that regulate the timing of VO will be among the important determinants of reproductive maturation in mice.

Moreover, it is possible that genes identified through CSS studies will play an important role in human development as well. Despite some species differences in pubertal physiology (3, 22), recent genetic findings have underscored the relevance of mouse studies to human biology. Homozygous defects in the ob gene (leptin), as in the ob/ob mouse, or in its receptor, as in the db/db mouse, result in genetic obesity and infertility characterized by persistent immaturity of the hypothalamic-pituitary-gonadal axis (23, 24). Congenital leptin deficiency and mutations in the leptin receptor are accompanied by absent pubertal development and hypogonadotropic hypogonadism in humans as well (25, 26, 27). Mutations in a G protein-coupled receptor, GPR54, have recently been identified as a cause of hypogonadotropic hypogonadism in humans (28, 29), whereas knockout mice fail to secrete GnRH and have permanent hypogonadotropic hypogonadism (29). Indeed, a review of the known genetic causes of hypogonadotropic hypogonadism in humans reveals that most of the defects show phenotypic fidelity in mouse models (30).

Our ultimate goal is to identify factors that regulate the HPG axis and determine the timing of puberty in the general human population. The CSSs are well suited for this task because the variants detected do not appear to alter the reproductive capacity of the CSSs; a CSS survey does not require a priori assumptions about candidate genes or pathways; and the CSSs provide the prospect of greatly facilitated QTL mapping because they are a renewable resource and each substitution resides on a defined and uniform genetic background (5, 9, 10). Thus, our finding that chromosomes 6 and 13 harbor loci that affect pubertal timing and the characteristics of the CSS panel suggest that this new genetic tool may lead to the identification of long sought after regulators of the HPG axis.


   Acknowledgments
 
We thank Drs. Huntington F. Willard, Matthew Warman, and Joel Hirschhorn for guidance and support throughout these studies. We also thank Ramon Jin for assistance in phenotyping the CSSs.


   Footnotes
 
This work was supported by National Institutes of Health Grants RR15544 (K23, to M.R.P.) and RR12305 (to J.H.N.).

Abbreviations: CSSs, Chromosome substitution strains; HPG, hypothalamic-pituitary-gonadal; QTLs, quantitative trait loci; VO, vaginal opening.

Received April 28, 2004.

Accepted for publication July 20, 2004.


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 Introduction
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals