Mouse models for identifying genes modulating fertility parameters Paul Laissue, D. l’Hote, Catherine Serres, Daniel Vaiman To cite this version: Paul Laissue, D. l’Hote, Catherine Serres, Daniel Vaiman. Mouse models for identifying genes modu- lating fertility parameters. animal, Published by Elsevier (since 2021) / Cambridge University Press (until 2020), 2009, 3 (1), pp.55-71. 10.1017/S1751731108003315. hal-02661605 HAL Id: hal-02661605 https://hal.inrae.fr/hal-02661605 Submitted on 30 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Animal (2009), 3:1, pp 55–71 & The Animal Consortium 2008 animal doi:10.1017/S1751731108003315 Mouse models for identifying genes modulating fertility parameters - P. Laissue1,2,3*, D. L’Hoˆ te1,2,3*, C. Serres1,2,3 and D. Vaiman1,2,3,4 1INSERM U567, Team21 ‘Genomics and Epigenetics of Placental Diseases’, Genetics and Development Department, Institute Cochin, 24 rue du Faubourg St-Jacques, 75014 Paris, France; 2CNRS UMR8104, Institute Cochin, 24 rue du Faubourg St-Jacques, 75014 Paris, France; 3Faculte´ de Me´decine Cochin-Port-Royal, Universite´ Paris Descartes, 24 rue du Faubourg St-Jacques, 75014 Paris, France; 4INRA Animal Genetics Department, France (Received 15 November 2007; Accepted 20 June 2008; First published online 8 October 2008) Fertility can be defined as the natural capability of giving life. It is an important factor both for human medicine, where ,10% of the couples call for the services of assisted reproductive technologies, and for species of economic interest. In particular, in dairy cows, the recent years have seen a kind of competition between milk production and fertility, and genes improving fertility are now considered as parameters to be selected for. The study of fertility pathways is nevertheless made difficult by the strong impact of environmental factors on this parameter, as well as by the number of genes potentially involved (as shown by systematic transcriptome analysis studies in the recent years). One additional level of complexity is given by the fact that factors modulating fertility will probably be sex specific. The usage of mouse models has been one of the solutions exploited for tackling with these difficulties. Here, we review three different approaches using mice for identifying genes modulating fertility in mammals: gene invalidation, positional cloning and in vitro mutagenesis. These three approaches exploit specific characteristics of the mouse, such as the possibility of controlling precisely the environment, an excellent genetic characterization and the existence of genomic and molecular tools equalled only in humans. Many indications suggest that at least some of the results obtained in mice could be easily transposed to the species of interest. Keywords: fertility, mice, gametogenesis, cattle, humans Introduction obvious target for selection to play with. Such selection pressure is presumably an important reason why, despite the Inherent complexity of the sexual reproduction and its complexity of the reproductive system, things seem to work implications in evolution pretty well. Mammalian reproduction encompasses several highly con- voluted phases: gamete production, gamete encounter and fusion, early development, implantation and post-implanta- Cost/benefit of sexual reproduction: the example tion developmental stages. These intertwined phases involve of high-producer dairy cows the modification and put on gear thousands of genes. This From an evolutionary point of view, two contradictory fact, which is not a posteriori surprising, was nevertheless trends seem to be at work in mammalian reproduction: considerably underestimated before the setting up of pan- an irreducible complexity for fabricating male and female genomic approaches of gene expression analysis carried out gametes in order to allow the fecundation and the vital from the early events of sex determination (Nef et al., 2005; necessity of the system for the mere survival of the species. Beverdam and Koopman, 2006; Cederroth et al., 2007) to In this context, another parameter can be taken into implantation (Giudice, 2003; Talbi et al., 2006). Any improper account concerning the instance of energy and resource regulation in either phase of the highly complex network of allotment. Indeed sexual reproduction is a costly method of genes involved may lead to infertility. The selection pressure survival, especially in female mammals, where the normal applied to reproduction is huge and if fitness is defined as follow-up of fecundation consists of long-lasting hosting of the capability of producing living offspring, then fertility is an one or several greedy foetuses. This essential biological and evolutionary condition is made even more severe by the fact * PL and DL contributed equally to the redaction of this paper. that parturition in most mammalian species is followed by - E-mail: [email protected] thecareoftheoffspringduringweeks,monthsorevenyears. 55 Laissue, L’Hoˆ te, Serres and Vaiman All these drawbacks are therefore to be counter-balanced by an increased fitness. Recently, the true cost of prolificacy has been illustrated by dairy cows producing ever higher amounts of milk (from 2500 kg in 1945 to almost 9000 kg a year today). This evolution has been particularly rapid in the last 20 years and it is estimated at 3000 kg from 1986 to 2006. In parallel and sometimes controversially, infertility has started to be a significant problem in cattle farming, evocating a potential antagonistic relation opposing fertility and high production, albeit up to now such a negative relationship has not been strictly demonstrated (Lopez-Gatius et al., 2006; Garcia-Ispierto et al., 2007). Elucidating the genetic control of reproductive functions is a Figure 1 One of the main interests of using mice as animal models is the difficult challenge fact that they are available as strains, meaning that their chromosome Heritability of reproductive parameters. The heritability of content is homozygous at every locus. Intra-strain crosses are largely reproduction parameters remains relatively elusive but most comparable to the mating of cloned animals, which, genetically speaking, reports suggest that it is either very low (0.05 or less) or should yield only identical animals, but the rare events of point mutations. By contrast, outbred species such as humans or species, which have weak (less than 0.20) (Bergmann and Hohenboken, 1992; been heavily selected for agricultural traits, have a strong level of Jamrozik et al., 2005; Bormann et al., 2006). Two likely heterozygosity. In the figure, homozygous regions are shown by brackets. reasons for this may be either a very strong influence of For traits displaying a low heritability, either because they are genetically external factors (light, temperature, hormonal and dietary ill-defined or because environmental factors play a major role, crosses between mice species are very useful, since environmental conditions can status) on the phenotype, which makes it difficult to isolate be very precisely controlled, and because the genetic diversity is obtained the genetic component of the observed variance, or a very by crossing existing strains, or by analyzing recombinant congenic strains. high underlying genetic complexity. General statements on human infertility treatments.In mouse, characterized by its short generation time, high humans, infertility affects up to 10% of the couples in prolificacy and small size (Figure 1). The debate of trans- industrialized countries (Feng, 2003) and the complexity of porting data from mice to humans or other species is the underlying biological disorders remains largely controversial and never-ending. However, it should be unknown at the molecular level. The responses brought to recognized that many advances on mammalian physiology the patients involve technological approaches based upon and genetics originate from mouse studies. two essential techniques: in vitro fecundation (IVF) and Reproduction has not escaped this reality and several intra-cytoplasmic sperm injection (ICSI). These approaches research groups around the world use laboratory mice to are meant to alleviate or escape the problems encountered evaluate fertility parameters. One of the important char- during gamete production, gamete encounter and fusion, acteristics of laboratory mice is that they exist as strains, early development and implantation. Such therapeutics, a collection of genetically identical animals. These strains generally based upon gamete and/or embryo manipula- show complete homozygosity at all genomic loci, of course tions, bring immediate solution to patient’s infertility but higher than in clones, which can be heterozygous at moves the possible genetical basis of the fertility problem numerous loci. This situation lessens considerably the to the next generation (Cram et al., 2000; Meschede et al., potential influences of individual genetic heterogeneity 2000). compared with other species. Different types of mouse models have been constructed corresponding