Molecular Human Reproduction, Vol. 8, No. 1, 1-7,
January 2002
© 2002 European Society of Human Reproduction and Embryology
Review |
Genetic approach to male meiotic division deficiency: the human macronuclear spermatozoa
Laboratoire de Cytologie et Histologie, EA1533, UFR Biomédicale des Saints Pères, 45, Rue des Saints Pères, 75006 Paris, France
To whom correspondence should be addressed at: E-mail: denise.escalier{at}biomedicale.univ-paris5.fr
Abstract
Human macronuclear spermatozoa (also termed large-headed or macrocephalic spermatozoa) are tetraploid and represent a mammalian model of meiotic division deficiency (MDD). Their genetic origin is strongly suggested by the existence of familial cases. They arise from spermatocytes I with a blockage of organelle displacement at the pachytene stage which disables the assembly of a bipolar meiotic spindle. Spermiogenesis can sometimes be complete, showing that meiotic divisions and spermiogenesis can be decoupled. However, the microtubular manchette is unilateral leading to an irregular sperm nucleus. A severe MDD phenotype also exhibits atrophic flagella. Another MDD phenotype is characterized by arrest at the round spermatid stage, suggesting the existence of factors coordinating meiosis and spermatid differentiation. An attempt is made herein to understand why MDD spermatocytes escape the pachytene and spindle-assembly checkpoints. These human MDD are revisited in the light of Drosophila mutants for cell cycle factors, meiosis division-promoting factors and microtubule components. Several human genes are known to be homologous to genes involved in male MDD in Drosophila mutants, and their number will soon be increased. These candidate genes open the way to investigation of human genes possibly mutated in patients with macronuclear spermatozoa and/or macronuclear spermatids.
meiosis/spermatogenesis/spermatozoa/sterility/testis
Introduction
The first case of a human sperm syndrome characterized by spermatozoa with a large head and multiple flagella was reported in 1977 (Nistal et al., 1977). A quantitative morphological study of six cases revealed a four-fold increased sperm nuclear volume and four flagella per spermatozoon (Escalier, 1983
). Therefore, these macrocephalic spermatozoa corresponded to the cell content of four spermatids and could be 4N DNA (Escalier, 1983). The presence of four copies of the genome in macrocephalic spermatozoa has been supported by three-colour fluorescent in-situ hybridization for chromosomes X, Y and 18 (Pieters et al., 1998). Surprisingly, the spermiogenesis events occurred normally, except that the microtubules (MT) of the manchette were found only on one edge of the nucleus (Escalier, 1985). Both the unilateral manchette and the giant nucleus induced a cascade of defects such as irregularity of the nuclear and acrosomal shapes and inability of some flagella to find a position for their anchorage. Some spermatozoa contained two closely apposed nuclei (mean, 11%) (Escalier, 1983). Examination of testicular biopsies revealed that these large-headed spermatozoa originated from germ cells that did not undergo the two meiotic divisions (type 1 phenotype) (Escalier, 1985). Subsequently, another human syndrome with failure of meiotic division was found to stop spermiogenesis at the round spermatid stage, giving rise to arrested macronuclear spermatids (type 2 phenotype) (Escalier et al., 1992). In this review, these human spermatogenesis syndromes are abbreviated as MDD for meiotic division deficiency. A genetic disorder was suggested by the finding of two brothers with the MDD phenotype (type 1, unpublished data) and by a study in which half of the patients had a history of male family members with infertility (Kahraman et al., 1999).
Meiosis anomalies characterizing human macronuclear spermatozoa and arrested macronuclear spermatids
Kallio et al. (1998) described the formation pathway of the male-specific meiosis I spindle in rodents (Kallio et al., 1998). The spindle begins by MT nucleation from two centrosomes located at a short distance and forming a mini-spindle. At the time of nuclear envelope breakdown, the chromosome bivalents form a cup-shaped structure with a small indentation or entry gap for the spindle. When the spindle completely invades the chromosome mass, the bivalents accumulate around it and the initial MT–kinetochore connections are made. At this step, only one of the two kinetochores is attached. The arms of the paired chromosomes point away from the centre of the spindle. Subsequently, the bivalents become connected to both poles and are orientated in the MT axes. Finally, the centrosomes separate, the spindle elongates forming a bipolar spindle and the chromosomes move together toward the spindle equator.
In the light of these important data, the meiotic division anomalies reported several years ago in the human can now be better understood. The comparison is attempted considering that the ancestral character of the meiotic divisions could implicate conserved meiotic division events between rodents and the human, with the reservation that conservation of the meiotic events considered remains to be demonstrated. In human MDD spermatocytes, the chromosomes condensed and were arranged in bivalents, the nuclear envelope breakdown occurred and the spindle was either short or slightly elongated. However, two spindle poles were never observed, suggesting that the centrosomes failed to separate or duplicate (Escalier, 1985). Considering the meiotic division pathway defined by one group (Kallio et al., 1998), the meiotic division features present in the human syndromes corresponded to the initial steps of prometaphase, the step of cup-shaped bivalents and of the short spindle integrated inside the cup-shaped bivalents (Escalier, 1985). Bivalents disposed in a plane were frequently seen (Escalier et al., 1991), and some kinetochore structures seemed to form (Figure 6c in Escalier, 1991). However, the subsequent steps of the prometaphase were never seen and anaphase and telophase were absent. Some of these spermatocytes were arrested and were found in the seminiferous tubule lumen with aggregated chromosomes in a plane (Escalier et al., 1992).
An intriguing finding was that anomalies of meiosis in the human were observed as early as the meiotic prophase I stage in type 2 MDD (not investigated in type 1 MDD) (Figure 1), as revealed by a study on proacrosin behaviour in cases of anomalies of human spermatogenesis. Proacrosin was found in the Golgi complex of spermatocytes I and II, allowing observation of Golgi partitioning during meiosis (Escalier et al., 1991). The localization of proacrosin in the Golgi complex of the spermatocytes was confirmed by transgenesis (Ventelä et al., 2000). In normal primary spermatocytes, the Golgi complex begins its partition at the mid-pachytene I stage and then separates into two bodies which move around the nucleus to be located at opposite nuclear poles. Later, the Golgi bodies are present in the plane, and at opposite sides, of the metaphase plate (Escalier et al., 1991; Oke and Suarez-Quian, 1992). In MDD spermatocytes, the Golgi complex totally failed division and movement at the prophase stage. At the entry into meiotic division, the unpartitioned Golgi was found at one edge of the mass of bivalents (Escalier et al., 1991, 1992).
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Therefore, the spermatogenesis anomalies in cases of human macronuclear spermatozoa or spermatids are a failure of Golgi partition and displacement before the nuclear envelope breakdown, and before failure of centrosome duplication or separation, and formation of a monopolar MT spindle and of a unilateral MT manchette (Figure 1
). Which meiotic process deficiency could impair meiotic divisions in human males?
In somatic cells, cell cycle displacements of organelles require destabilization and disassembly of the MT network around the nucleus (Lieuvin et al., 1994; Ebneth et al., 1999; Thyberg and Moskalewski, 1999) and mitotic kinases that interact with and phosphorylate organelle-associated proteins (Sütterlin et al., 2001). Spermatocytes at the pachytene stage display MT bundles in close association with the Golgi apparatus (Moreno and Schatten, 2000). Anomalies of tubulins and MT-associated kinases in mammalian male germ cells arrested in metaphase I have been demonstrated in the mouse following overexpression of the v-Mos oncogene (Rosenberg et al., 1995). Therefore, blockage of organelle partitioning in pachytene spermatocytes from MDD men could be due to a failure of MT disassembly and/or disruption of a meiotic kinase involved in organelle partition.
Competence for meiotic division arises during the mid-pachytene stage, is coincident with the accumulation of the cell cycle regulatory protein Cdc25c and requires the mitosis-promoting factor (MPF) (p34cdc2/cyclin B complex) and topoisomerase II (Handel et al., 1999). It is noteworthy that blockage of the translation of MPF induces an arrest of the primary spermatocytes at the G2 to M phase transition (Kong et al., 2000). Cell cycle regulating factors for the control of male meiosis in mammals are found to be highly expressed in pachytene spermatocytes (Letwin et al., 1992; Hazan et al., 1993; Wickramasinghe et al., 1995; Wolgemuth et al., 1995; Rhee and Wolgemuth, 1997; Nakamura et al., 1999; Sette et al., 1999; Godet et al., 2000; Kim et al., 2001). Therefore, long before their M phase, the spermatocytes accumulate cell cycle factors and enzymes necessary to trigger the division and prepare for spindle building and organelle partition. A defect in one of these numerous factors could lead to human MDD spermatocytes, as shown in Drosophila mutants (see below). The absence of somatic syndrome(s) in the patients suggests that such a factor should be meiosis-specific.
The possible origin of the human male MDD could be explained from another point of view, although this could concern the same cell cycle factors as in the interpretation presented above. A prophase delay at the pachytene stage of spermatocytes I would allow recombination to occur. The factors controlling exit from this delay and allowing organelle partitioning are not yet identified (Oke and Suarez-Quian, 1992), except that Cdc kinases accumulate at this step and should act in the MT destabilization. The human MDD spermatocytes could be unable to trigger the cytoplasmic factors normally associated with the exit from prophase delay, and therefore might be unable to remove the MT stabilizing factor that could maintain spermatocytes I in prophase.
Human MDD spermatocytes escape two meiotic checkpoint controls
The pachytene checkpoint is normally induced by DNA damage, and is activated by Cdc2 and the protein kinase Wee1 (`wee' is a Scottish word for `small') that phosphorylates and inactivates Cdc28 and leads to spermatocyte I apoptosis (Roeder and Bailis, 2000). The human Wee1B is particularly abundant in testis (Nakanishi et al., 2000). The absence of activation of the pachytene checkpoint in human male MDD suggests that the spermatocytes did not share DNA damage, supporting the hypothesis of anomalies of cytoplasmic events in spermatocytes I.
During mitosis, the spindle-assembly checkpoint forces anaphase to wait until homologues are properly attached to the spindle by kinetochores. Unattached kinetochores generate an inhibitory signal that blocks the transition to anaphase by inhibiting the activity of the ubiquitin ligase of the anaphase-promoting complex (APC) (Page and Hieter, 1999; Maney et al., 2000; Wassmann and Benezra, 2001). APC factors are involved during meiosis (Salah and Nasmyth, 2000) and the presence of a spindle-assembly checkpoint during meiosis in male Drosophila is now substantiated (Rebollo and Gonzalez, 2000). In the case of human MDD spermatocytes, events that do not occur are bivalent two-pole attachment, bivalent orientation required for anaphase promotion and an incomplete set of kinetochores. Such defects should activate the spindle-assembly checkpoint, which should then lead to the elimination of all spermatocytes from MDD patients. A possibility is that the early anomalies of MDD spermatocytes could be responsible for silencing of the spindle checkpoint factors that are normally activated later, at the metaphase plate step. Another possibility could be that the spindle-assembly checkpoint could be activated but unable to function due to extensive spindle anomalies. Finally, the primary defect in human MDD could be a factor that also normally triggers germ cell elimination. Whatever the case, the human MDD shows that passage through the several steps of meiosis is not required for the initiation and completion of spermiogenesis (Escalier, 1999b).
MDD in Drosophila male sterile mutants
Twenty per cent of Drosophila male sterile mutants have more or less distinct germ cell phenotypes that are similar to those described for the mouse or the human (Hochstenbach and Hackstein, 2000) and Drosophila is particularly suited as a model organism for the study of spermatogenesis in man (Hackstein et al., 2000).
Most of the anomalies of the meiotic divisions of spermatocytes have been described from Drosophila mutants. Two MDD categories can be distinguished. The first corresponds to spermatids with a polyploid nucleus due to complete failure of meiotic spindle function (Table I). The other mutations are related to multinucleated spermatids suggesting partial spindle activity leading to a variable number of nuclei and nuclei of various sizes (not considered here, see note in Table I). Mutations leading to a unique polyploid sperm nucleus show different pathways of arrest depending on the gene affected, and these can be informative for comparison with the human MDD syndromes.
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Mutants for the testis-specific ß2 tubulin present anomalies of MT-mediated events leading to abnormal giant sperm heads and anomalies of the axonemal assembly (Kemphues et al., 1982
). The extent of the MT defects depends on the ß2 tubulin alleles, as some are partially functional (Fuller et al., 1988). That some human males cumulate both MDD and axonemal anomalies (type 3 MDD) strengthens the hypothesis of an anomaly of a testis-specific tubulin in these cases (Escalier, 1983).
Mutation in the mgr gene (merry-go-round) causes metaphase arrest with over-condensed chromosomes arranged in a circle and absence of meiotic spindles. Spermatids with mitochondrial disorganization degenerate during early stages of elongation (Gonzàlez et al., 1988).
Twine is a Cdc25-type phosphatase homologue, that is specific for meiosis and that activates the cell-cycle Cdc2 kinase (Maines and Wasserman, 1999). Twine is necessary for the association of 
-tubulin Tub23C at centrioles during the transition into the first meiotic division (Wilson et al., 1997). Twine mutants exhibit absence of meiotic divisions but retain the ability to perform spermiogenesis, although no mature spermatozoa are formed (Courtot et al., 1992; Maines and Wasserman, 1998). Surprisingly, Cdc25C knock-out mice are fertile. It is unknown whether Cdc25A and/or Cdc25B compensates for lack of Cdc25C or whether other compensatory mechanisms exist in mice lacking Cdc25C (Chen et al., 2001). Drosophila mutants for the temperature-sensitive Cdc2 kinase allele exhibit the same phenotype as twine mutants (Sigrist et al., 1995).
Pelota is the Drosophila homologue of DOM34, a gene of Saccharomyces cerevisiae that acts in ribosome function and bulk protein translation (Davis and Engebrecht, 1998). Mutations of some pelota alleles induce anomalies similar to those of twine (Eberhart and Wasserman, 1995). The chromosomes partially condense, but never move away from the nuclear periphery. The centrosomes do not complete their migration and a spindle is never observed. Nuclear envelope breakdown does not occur. Spermatid nuclei form wedge-shaped heads not attached to the tails. Twine and pelota are distinct since heterologous expression of twine does not restore meiotic entry in males with pelota mutations (Maines and Wasserman, 1999). Moreover, homozygous mutant flies for strong pelota alleles are also affected by eye defects (Eberhart and Wasserman, 1995). Of particular interest is the finding that human pelota cDNA (PELO), a single copy gene on chromosome 5q11.2, gives an additional 2.0 kb transcript in testis (Shamsadin et al., 2000).
Mutants for aly (always early), can (cannonball), mia (meiosis I arrest) or sa (spermatocyte arrest) fail to undergo either meiotic divisions or spermatid differentiation (Lin et al., 1996). It has been suggested that a gene or genes transcribed under the control of can, mia and sa may act to allow translation or stabilization of twine and that Aly is required for the transcription of cyclin B and twine (Fuller, 1998; for review). Aly also regulates spermatid differentiation by controlling transcription in spermatocytes I of spermatid differentiation genes, and Aly is a member of a protein family conserved from plants to humans (White-Cooper et al., 2000).
Boule (an RNA-binding protein) is expressed only in the testis and mutation of boule blocks both meiotic divisions leading to tetraploid spermatids that fail to mature into spermatozoa. Boule mutants carry out chromosome condensation and centrosome duplication but are incapable of spindle formation, nuclear lamina breakdown, or chromosome disposition at the metaphase plate (Eberhart et al., 1996). Also Boule may be required in coordinating meiosis and spermatid differentiation. Heterologous expression of twine rescues the boule meiotic entry defect, indicating that Boule controls Twine translation. Mutations in mia or sa result in a failure to accumulate Boule protein (Maines and Wasserman, 1999). It is therefore considered that sa and mia act upstream of boule and that twine acts downstream of boule (Maines and Wasserman, 1999). The true mammalian orthologue of boule has been recently identified in the human and the mouse (Xu et al., 2001). Before this finding, the mouse Dazla gene (autosomal Daz gene) was considered as the boule orthologue in mammals. However, disruption of Dazla leads to another phenotype characterized by spermatogonia arrest (Ruggiu et al., 1997). This suggests that Dazla has evolved a novel pre-meiotic function unique to vertebrates (Xu et al., 2001).
In summary, Drosophila mutants show that numerous genes can be related to a complete failure of meiotic divisions during spermatogenesis. These genes are related to MT components, cell cycle enzymes and also to RNA-binding factors that control translation and stabilization of cell cycle operators for the cascade of meiosis events. An anomaly of phosphorylation of MT-related structures in spermatocytes I could explain a failure to perform the two meiotic divisions as found in type 1 MDD spermatozoa. The factor involved could be a meiosis-specific MT-associated component (tubulin, microtubule-associated protein, motor protein) or a meiosis-specific cell cycle regulating factor (Cdc, kinase, cyclin). Drosophila mutants suggest that meiosis-specific Cdc kinases control male meiotic divisions and that these kinases are under the control of other factors that can also control the progress of spermiogenesis. The existence of factors coordinating meiosis and spermatid differentiation could explain the type 2 MDD human phenotype. Drosophila mutants show that testis-specific MT components can be involved in the building of both the meiotic spindle and the flagellum and that more penetrating mutations of genes for these MT components lead to a more severe pleiotropic phenotype in MDD males, as found in type 3 MDD human spermatozoa.
Disclosing the secret of human macronuclear spermatozoa: perspectives for future research
Knowledge of factors involved in mitosis and meiosis and Drosophila mutants sheds light on the intriguing phenotypes of human spermatozoa arising from spermatocytes unable to perform meiotic divisions. The most intriguing finding concerning these pleiotropic human germ cell phenotypes is the existence of anomalies related to the perinuclear compartment affecting organelle displacement or distribution, such as the Golgi, the centrosomes and the manchette. These anomalies could furnish the key for locating the affected factor. Investigations, in human MDD spermatocytes, of cell cycle proteins expressed during the G2 phase, the G2/M phase and the pre-metaphase could furnish information on the status of their cell cycle events and could help to choose the genes to be investigated.
The phenotypes of tetraploid spermatids or tetraploid spermatozoa have not yet been produced by genetic engineering in mammals, although more than 120 different knock-out mice are now known to present anomalies of spermatogenesis associated with infertility (Escalier, 1999a, 2001). This includes inactivation of 17 genes acting directly or indirectly in the meiotic events and genes of MT components (space is lacking for a review of these in the present study). However, it is premature to exclude some of these genes as candidates for the MDD syndrome because of possible functional differences of these genes between the human and the mouse. Moreover, embryo death characterizes mice defective in cyclin A2, cyclin B1 or polo-like kinase (Cdc5) (Murphy et al., 1997; Brandeis et al., 1998; Hudson et al., 2001), precluding the knowledge of the status of spermatogenesis in these mice. It is noteworthy that male MDD has been found in a family with recurrent death of embryos or newborns (Professor J.P.Wolf, personal communication), suggesting that somatic cell cycle factors could also be involved in some cases of macronuclear spermatozoa. The explanation could be the involvement of strong alleles or more penetrating mutations in the occurrence of more severe pleiotropic phenotypes, as seen in some Drosophila mutants (see above).
Mouse models suggest that there are functional divergences of homologous genes between Drosophila and mice as a result of co-option of a gene during evolution for a new function (Escalier, 2001). Nevertheless, some Drosophila genes known to impair meiotic divisions in the male could be candidates for human male MDD, particularly those that are testis-specific. The extending generation of knock-out mice should favour the production of similar germ cell phenotypes and should lead to knowledge of the gene(s) implicated. Moreover, new Drosophila genes involved in male meiosis divisions are on the point of being identified and their human homologues will be identified soon thereafter. This opens the way to investigation of the human genes possibly implicated in male MDD.
Acknowledgements
I thank Prof. J.P.Dadoune (Université Paris 6) for helpful comments on the manuscript and Mme Doreen Broneer (Hopital Necker, Paris) for help with the English language. I apologize to those investigators whose work was not cited, or cited only through reviews, due to the brevity of this review.
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Submitted on March 21, 2001; accepted on October 11, 2001.
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