Human Reproduction Update Advance Access originally published online on March 24, 2006
Human Reproduction Update 2006 12(4):449-461; doi:10.1093/humupd/dml013
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Knockout mouse models of sperm flagellum anomalies
Andrology Department, University Paris XI, CHU Kremlin Bicêtre, France
To whom correspondence should be addressed at: Laboratoire d’Histologie Moléculaire et Fonctionnelle, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France. E-mail: denise.escalier{at}univ-paris5.fr
Submitted on January 18, 2006; resubmitted on February 21, 2006; accepted on February 28, 2006
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Abstract |
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 TOP Abstract IntroductionTargeted factors in KO...Other factors possibly involved...ConclusionReferences |
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To date, 21 knockout mouse models are known to bear specific anomalies of the sperm flagellum structures leading to motility disorders. In addition, genes responsible for flagellar defects of two well-known spontaneous mutant mice have recently been identified. These models reveal genetic factors, which are required for the proper assembly of the axoneme, the annulus, the mitochondrial sheath and the fibrous sheath. Many of these genetic factors follow unexpected cellular pathways to act on sperm flagellum morphogenesis. These mouse models may bear anomalies which are restricted to the spermatozoa or display more complex phenotypes that often include neuropathies and/or cilia-related diseases. In human, several structural disorders of the sperm flagellum found in brothers or consanguineous men probably have a genetic origin, but the genes involved have not yet been identified. The mutant mice we present in this review are invaluable models, which can be used to identify potential candidate genes for infertile men with specific sperm flagellum anomalies.
Key words: axoneme / flagella / knockout mice / mutant mice / spermatogenesis / spermatozoa
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Introduction |
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TOPAbstractIntroductionTargeted factors in KO...Other factors possibly involved...ConclusionReferences |
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Over time, many anomalous mouse sperm phenotypes have been discovered in spontaneous mutants (Dooher and Bennett, 1974
; Bryan, 1977; Bennett, 1981). But it is only recently that knowledge of the mouse genome has allowed the identification of particular genes involved in specific sperm anomalies. Additionally, the identification of an increasing number of genes that are expressed only in the testis has enabled the creation of various sterile male mouse models by genetic engineering. Moreover, most of the male sterile knockout (KO) mice were identified after the targeting of genes was not yet known to play a role in male reproduction. These mouse models have considerably increased our knowledge of the genetic factors that are necessary for male reproduction and, more particularly, for the completion of spermatogenesis. In the beginning, the targeted genes were related to factors of endocrine, cell cycle and meiosis pathways (Venables and Cooke, 2000; Wolgemuth, 2003). Consequently, the first reviews on KO mice with spermatogenesis impairment did not include models for specific sperm flagellum anomalies (Cooke et al., 1998; Grootegoed et al., 1998; Okabe et al., 1998). Reviews including KO mice with impairment of sperm flagellum morphogenesis or motility were published later (Escalier, 1999, 2001; Cram et al., 2001; Matzuk and Lamb, 2002; Toshimori et al., 2004). To date, approximately 300 KO mouse models have been reported to display male reproduction disorders, of which 36 (12%) have spermatozoa with impaired motility, including 21 KO mouse models with sperm flagellum structure anomalies and 15 KO mice with apparently normal flagellar structures. This review presents 23 mutant mice with specific anomalies of the structures of the sperm flagellum and leading to asthenospermia, dyskinesia or total immobility. Among them are two spontaneous mutant mice with a long-known sperm flagellum anomaly, for which the genes involved have now been identified. At least 25 other KO mice with predominant anomalies of the sperm head morphogenesis have been described that also exhibit anomalies of the flagellum, such as coiling, retro-flexion, angulation and disconnection. These KO mice with common sperm flagellum anomalies are not considered in this review. The structure of the mouse spermatozoon flagellum is presented in Figures 1 and 2. Some previously known functions of the genes considered are summarized in Table I and the phenotype of the KO mice in Table II.
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Targeted factors in KO mice with specific flagellar anomalies |
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TOPAbstractIntroductionTargeted factors in KO...Other factors possibly involved...ConclusionReferences |
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Bbs
The Bardet–Biedl syndrome (BBS) is a pleiotropic human disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism. BBS patients also have an increased incidence of diabetes mellitus, hypertension and congenital heart disease (Katsanis, 2004; Beales, 2005). Nine BBS genes have been identified (Nishimura et al., 2005), and a BBS2 missense mutation has been found in two homozygote adult male patients with severe oligoteratoastenozoospermia, necrozoospermia and anomalies of the sperm acrosome, nucleus and axonemal structures (Nishimura et al., 2001). BBS4, BBS5 and BBS8 localize to cilia-related structures, particularly to the basal bodies (Ansley et al., 2003; Li et al., 2004). This suggested that some BBS genes could be involved in basal body dysfunction (Ansley et al., 2003). Cilia of Caenorhabdtitis elegans mutants for homologues of BBS7 and BBS8 lack the distal axonemal segments, and BBS7 and BBS8 have recently been found to be required to stabilize the intra-flagellar transport (IFT) particles in this species (Ou et al., 2005). IFT is known in Chlamydomonas as a rapid movement of multi-subunit protein particles along the microtubules that are required for assembly and maintenance of the flagella (Marshall et al., 2005).
Bbs2–/– (Nishimura et al., 2004) and Bbs4–/– (Mykytyn et al., 2004) mice have a similar phenotype characterized by retinal degeneration through apoptosis, obesity associated with increased food intake and polycystic kidney disease. They also display neurological deficits including olfactory abnormalities and a defect in social dominance. Males are infertile, and the spermatids fail to produce a flagellum.
The McKusick–Kaufman syndrome (MKKS) is an autosomal recessive disorder characterized by polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. MKKS is a hypomorphic variant of BBS with a complex heritance. Unlike BBS patients, MKKS patients are not obese and do not develop retinopathy or have learning disabilities (Katsanis et al., 2000; Slavotinek et al., 2000), and MKKS (alias BBS6) may be a type II chaperonin implicated in the facilitation of nascent protein folding (Katsanis et al., 2001). Mkks null mice have retinal degeneration through apoptosis, high blood pressure, obesity and deficits in olfaction and in social dominance. The obesity is associated with hyperphagia and decreased activity. The phenotype of the Mkks null mice closely resembles the phenotype of Bbs2–/– and Bbs4–/– mice, including a complete failure of the formation of a sperm flagellum (Fath et al., 2005).
The dynein molecular motor generates the movement of motile cilia and flagella. The dynein heavy-chain (Dnahc) polypeptides assemble with the dynein intermediate (Dnai) and light (Dnal) chains into multiprotein complexes to form outer and inner dynein arms (ODA and IDA, respectively) which are attached to the axonemal microtubules (Figure 1). Dnahcs form the globular heads and the stem of the complexes and contain the ATPase and microtubule motor domains (Inaba, 2003).
Primary ciliary dyskinesia (PCD) is a human disorder characterized by recurrent respiratory infections, infertility and randomization of left–right asymmetry in the Kartagener syndrome (Carlen and Stenram, 2005). Hydrocephalus (Greenstone et al., 1984; al-Shroof et al., 2001; Kosaki et al., 2004) and renal disease (Laboudi et al., 2003) are found in a few patients. Anomalies of the dynein arms in cilia of the respiratory tract have been described in PCD patients (Afzelius et al., 1975; Afzelius and Eliasson, 1979; Baccetti et al., 1981; Escalier, 1982; Escudier et al., 1990). Numerous orthologues of Chlamydomonas dynein arm subunits have been found in the human (24 for the ODA and 12 for the IDA) (Pazour et al., 2006).
The axonemal IDAs consist of a set of three complexes, and Dnahc7 is a component of the IDA3 (Vernon et al., 2005). Dnahc7–/– mice were deleted for the central and C-terminal regions of the Dnahc7 (that include the ATP-binding site), and homozygous mice expressed a low amount of truncated Mdhc7 (Neesen et al., 2001). Male mice are infertile. The beat frequency of tracheal cilia is half of the normal value, but no infection of the respiratory tract appears. Dnahc7–/– spermatozoa are unable to move from the uterus into the oviduct, but they are able to fertilize eggs in vitro. Nevertheless, the number of eight cell stage embryos is reduced. Only 38% of the spermatozoa are motile and only 1% exhibits progressive movement. Motile spermatozoa have a reduction of about 50% of the beat’s lateral amplitude and a slight increase in beat frequency. In Dnahc7–/– spermatozoa, the IDA3 has only a single head (Vernon et al., 2005). When the sperm acquires motility in the epididymis, the outer dense fibres abnormally retain attachments to the inner surface of the mitochondria, suggesting insufficient force to overcome these attachments in Dnahc7–/– spermatozoa (Woolley et al., 2005).
Data on other axonemal dyneins
Interestingly, the testis-specific Dnahc8 (Tcd2) has been identified as a candidate for the hybrid sterility 6 (hst6) mice (Samant et al., 2002). In spermatozoa of Hst6 mice, the axonemal and peri-axonemal components of the flagellum are totally scattered in a cytoplasmic mass (Phillips et al., 1993). The t-complex also contains dynein light chains tctex1 (IDAs) and tctex2 (ODAs) (Schimenti, 2000).
Mutations in dynein, axonemal, intermediate polypeptide 1 gene (DNAI1) (Pennarun et al., 1999; Bartoloni et al., 2002) and dynein, axonemal, heavy polypeptide 5 gene (DNAH5) (Olbrich et al., 2002) have been found in patients lacking ciliary ODAs (Pennarun et al., 1999), but these men were not infertile. Moreover, Dnahc5–/– mice die at 2–3 weeks of age precluding the observation of mature spermatozoa. As in the human, Dnahc5–/– mice lack ODAs in respiratory cilia and have a PCD-like phenotype (Ibanez-Tallon et al., 2002, 2004).
The tektin protofilament in the A tubule of the axonemal doublets is near the binding sites for radial spokes, IDAs and nexin links (Nojima et al., 1995; Larsson et al., 2000). Tektin-t is specific to spermatids and is expressed in the sperm tail (Iguchi et al., 1999). Spermatozoa of homozygous tektin-t mutant mice are unable to reach the oviducts of females but have the ability to fertilize eggs in vitro which subsequently develop to adulthood (Tanaka et al., 2004). In tektin-t–/– sperm, the proportion of motile spermatozoa is reduced, and their movement is affected with regard to average path velocity, straight-line velocity and curvilinear velocity. About 70% of the homozygous mutant sperm have abnormally bent flagella and a partial deficiency or loss of the IDAs. A variable number of IDAs are missing in respiratory cilia, which severely affects their activity. Female homozygous tektin-t mutant mice are normally fertile, even though they lack the IDAs in the cilia of the oviducts.
The sperm-associated antigen 6 (Spag6) is the murine orthologue of Chlamydomonas PF16. PF16 is characterized by eight contiguous armadillo repeat motifs that are involved in protein–protein interaction (Smith and Lefebvre, 1996). The flagella of the Chlamydomonas Pf16 mutant are paralysed, and the C1 axonemal central microtubule (Figure 1) is unstable (Dutcher et al., 1984). Also Spag6 is localized in the central apparatus of the flagellar axoneme. The quantity of Spag6 messenger RNA (mRNA) present in lung cells is low (Sapiro et al., 2000). In mammals, SPAG6, PF6 and SPAG16 form a complex that links components of the axoneme’s central apparatus together (Zhang et al., 2005).
Approximately 50% of the Spag6–/– mice (Sapiro et al., 2002) had retarded post-natal growth and died before 2 months of age with hydrocephalus. However, the ultrastructure of tracheal and ependymal cilia of Spag6–/– mice appears normal. Only 80% of the nullizygous females are able to conceive but with a delay in the time to pregnancy.
Surviving Spag6–/– males are infertile with 60% abnormal epididymal sperm (only 25% in the testis) that exhibit fragmentation of the midpiece, truncated flagella and sperm decapitation. The flagellar axoneme lacks the central pair of microtubules and doublets (anomalies not found in the testis). The outer dense fibres and the fibrous sheath (FS) are disorganized. A mean of 8% of recovered Spag6–/– sperm are motile, and very few of them show a progressive forward motion, being characterized by a reduced swimming speed and a quaking or twitching motion. Cytoplasmic masses with totally disorganized flagellar structures are present in the Spag6–/– seminiferous tubules. Sperm from Spag6+/– mice are fertile, although they have an intermediate value for sperm swimming speed (Sapiro et al., 2002).
In Chlamydomonas, PF20 is located in bridges connecting the C1 and C2 axonemal microtubules (Figure 1), and Chlamydomonas strains lacking PF20 have paralysed flagella and lack the axonemal central apparatus (Smith and Lefebvre, 1997). The murine Spag16 gene is the homologue of Pf20. Spag16 uses alternative promoters to transcribe two major mRNAs that encode the large (Spag16L) and the small (Spag16S) proteins. Spag16L is found in the cytoplasm of germ cells and in the axoneme central region of the sperm flagellum, whereas Spag16S is present in germ cell nuclei. Spag16S is found to interact with MEIG1, a chromosome/chromatin-binding protein that may participate in the regulation of chromosome structure and/or gene expression (Don et al., 1994).
Targeted disruption of Spag16 sequences encoding the C terminus of the large and small proteins results in severe impairment of spermatogenesis (Zhang et al., 2004). Most of the male mice are infertile because of haplo-insufficiency of Spag16, and they produce a mixture of spermatozoa containing the wild-type and mutant Spag16 alleles. Many seminiferous tubules contain either round spermatids undergoing apoptosis or only vacuolated Sertoli cells. Anomalies at the round spermatid stage may be because of lack of the nuclear Spag16S. The number of epididymal spermatozoa is markedly reduced. The average proportion of motile sperm is 23%, and epididymal spermatozoa with the targeted allele have bent tails and a quaking motion. Between 27 and 31% of sperm axonemes lack the axonemal central pair (only 6.4% in the testis), and 14–16% display disorganization of outer doublet microtubules and outer dense fibres (only 3.2% in the testis). Data suggested that the Spag16 gene is involved in the survival of post-meiotic germ cells and the maintenance of the integrity of the sperm axoneme and associated structures.
Mice deficient in only Spag16L have been generated (Zhang et al., 2005). Spag16L–/– are infertile, but only half of these mice exhibit a spermatogenetic defect, particularly degenerating germ cells. The number of sperm is half that of wild-type males, and only 25% of the spermatozoa are motile. The flagellar movement is limited to a slow, erratic waveform with a curvilinear velocity near half the normal value, suggesting a defect in the attachment of the spoke heads to the central pair apparatus or deformation of this structure. The ultrastructure of the flagellar axoneme is normal. The different phenotypes of these two Spag16 mouse models indicate that it is the nuclear Spag16S that causes the serious deficiency in spermatogenesis seen in males in which both Spag16L and Spag16S are eliminated.
Neuralized acts in a subset of Notch-dependent cell-fate decisions, including lateral inhibition in Drosophila neurogenesis (Kramer, 2001). Neuralized is required at the plasma membrane for functional activity, and its RING finger domain acts as an E3 ubiquitin ligase (Yeh et al., 2001). Neuralized-like homologue KO mice (Neur1–/–) (Vollrath et al., 2001) do not show aberrant cell-fate specifications in the central nervous system nor in the developing mesoderm. However, Neur1–/– females fail to lactate or successfully nurse their pups and have defective mammary gland development in the final stages of pregnancy. Male Neur1–/– null mice are sterile, and a large majority of their spermatozoa are immotile. About 30% of the axonemes are abnormal in cross-sections of the flagella principal piece. In fact the anomalies are discontinuous along the axoneme, suggesting a larger number of affected axonemes. One axonemal doublet (usually no. 7) or four doublets (usually no. 4–7) are missing. Other, less common, morphological defects include translocation of doublets outside of the axonemal complex, total disorganization of the axoneme and dislocation of dense fibres. In some spermatozoa, the FS is either malformed or absent in some flagellar regions. A large number of spermatozoa develop double, or sometimes triple, axonemes (also with anomalies), and isolated flagella are also present. Similar axonemal anomalies are found in the testis, in which some spermatids present an abnormal neckpiece. Headless sperm are also found in the testis. Another report on Neuralized null mice (Ruan et al., 2001) describes no anomaly of either male or female reproduction, which could be explained by different genetic strategies or the genetic background of the mice.
Voltage-dependent anion channels (VDACs) are located in the membranes of mitochondria and the sarcoplasmic reticulum of skeletal muscle. VDACs are important transporters of adenine nucleotides, Ca2+ and other metabolites into and out of mitochondria (Shoshan-Barmatz and Israelson, 2005). VDACs also serve as a binding site for cytosolic hexokinase (Cesar Mde and Wilson, 2004). Three genes encode VDAC1, VDAC2 and VDAC3 (Sampson et al., 1997). VDAC2 and VDAC3 are present in the flagellum of bovine spermatozoa (Hinsch et al., 2004).
Vdac3 null mice are healthy but have abnormally shaped skeletal muscle mitochondria and reduced activities of the respiratory chain complexes. The cilia in tracheal cells are motile, but although they are reduced in number, the mice do not exhibit respiratory conditions. Male mice lacking Vdac3 are infertile (Sampson et al., 2001). Flagella anomalies are rare in testicular sperm cells, but a loss of axonemal doublet no. 7 and its associated outer dense fibre is found in 68% of epididymal spermatozoa. Less frequently, flagella lack half of the axonemal doublets, with ectopically placed doublets and partial axonemal duplications. The mitochondria in the middle piece of spermatids are enlarged and abnormally shaped. Only 17% of Vdac3–/– sperm are motile and only 3% exhibit progression.
Quakingviable (qkv) is a recessive neurological mouse mutation characterized by a severe lack of myelin (Sidman et al., 1964), and qkv homozygous males are sterile because of a severe oligospermia (Bennett et al., 1971). Two genes map to the qkv deletion: Parkin, the mouse homologue of the human PARKIN gene (PRKN) and Pacrg, the homologue of a human gene termed PARKIN co-regulated gene (PACRG). Parkin is an E3 ubiquitin-protein ligase, and Pacrg is potentially linked to the ubiquitin/proteasome system (West et al., 2003).
PARKIN loss-of-function causes an autosomal recessive form of early-onset Parkinson’s disease (Kitada et al., 1998). Surprisingly, another type of parkin-deficient mouse does not present Parkinsonism (Perez and Palmiter, 2005). Mice lacking parkin are fertile (Goldberg et al., 2003; Itier et al., 2003). Both parkin and pacrg (also named Park2 co-regulated) are deleted in quaking mice (Lockhart et al., 2004). RNA interference knockdown of the two homologues of PACRG in Trypanosoma leads to loss of flagellar doublets (Dawe et al., 2005).
Transgenic expression of the mouse Pacrg complementary DNA in testes of qkv mice rescues the sperm differentiation defect and restores normal fertility in qkv males. This datum shows that Pacrg is the cause of male sterility in qkv (Lorenzetti et al., 2004). Pacrg is expressed in the round spermatids and at lower levels in pachytene spermatocytes. Pacrg is present in the sperm post-acrosomal region and the middle piece of the flagellum.
Spermatids fail to complete differentiation in qkv males, leading to few immotile spermatozoa with extensive indentations of the nucleus. In qkv spermatids, the flagellum begins to develop normally, then axonemal and peri-axonemal structures are scattered in a cytoplasmic mass (Bennett et al., 1971). Sperm from qkv semen and testes are unable to fertilize mouse oocytes in vitro. However, normal live offspring can be obtained by intracytoplasmic injection of qkv spermatozoa into mouse oocytes (Yanagimachi et al., 2004).
The recessive mouse mutant, Purkinje cell degeneration (pcd), shows a neurodegeneration that occurs after weaning, when most synaptic circuitries are established. Pcd mice exhibit moderate ataxia but lose retinal photoreceptor cells during the first year of life (LaVail et al., 1982). pcd1J is the original mutation leading to sterile male mice with non-motile abnormal spermatozoa (Mullen et al., 1976). The phenotypes pcd2J and pcd3J mice are nearly identical, except that many pcd2J homozygous males are fertile. The mouse pcd region contains Nna1 (nervous system nuclear protein induced by axotomy). It encodes ATP/GTP-binding protein 1 (Agtpbp1), a putative zinc carboxypeptidase that contains nuclear localization signals and an ATP/GTP-binding motif. Exon 8 of Nna1 is missing in pcd3J brain and testis. The reduced level of Nna1 mRNA may be sufficient to support spermatogenesis in pcd2J, but not in pcd1J (approximately 20-fold reduction) (Fernandez-Gonzalez et al., 2002). Nna1 is expressed throughout the brain, retina and in spermatids, consistent with the defective spermatogenesis in pcd.
The Jun family of activator protein-1 transcription factors (c-Jun, JunB and JunD) is involved in proliferation, apoptosis, tumour angiogenesis and hypertrophy. Mice populations lacking Jund1 have increased mortality rates and exhibit enhanced cardiomyocyte apoptosis and fibrosis (Hilfiker-Kleiner et al., 2005). Jund1 interacts with menin, a tumour suppressing factor, suggesting that Jund1 may play a role in growth inhibition (Angel and Karin, 1991). Jund1 is present in the epididymis, testicular interstitial cells, Sertoli cells, spermatocytes and spermatids.
Jund1–/– animals have a post-natal growth retardation with a 30% reduction in growth hormone (Thepot et al., 2000). The adult body weight is only 80–85% of wild-type littermates. Approximately 25% of Jund1–/– males do not produce litters, and they fail to exhibit any mating behaviour. More than half of the other Jund1–/– young male mice mate normally but cease to produce litters, as they become older.
Homozygous mutant mice exhibit either oligoasthenoteratospermia or asthenospermia. Spermatid heads have an abnormal hammer-like shape. There is a disorganization of the axoneme in the initial flagellum, and the axoneme components and peri-axonemal structures are totally scattered in a cytoplasmic mass in late spermatids (Thepot et al., 2000).
DNA polymerase lambda is a member of the X family of polymerases, which is implicated in non-homologous end-joining of double-strand breaks in DNA and in base excision repair (BER) of DNA damage. Also Pol-
exhibits 5'-deoxyribose phosphodiesterase (lyase) activity, and Pol- activity is regulated by the proliferating cell nuclear antigen and the tumour suppressor protein p21 (Garcia-Diaz et al., 2005). Pol- has been implicated in meiosis (Plug et al., 1997). Pol- is detected in several tissues and is abundantly expressed in the testis, mainly in late pachytene spermatocytes (Garcia-Diaz et al., 2000). Mice deleted in Pol- have been reported (Kobayashi et al., 2002). However, Pol-–/– mice are also deleted in the first exon of Dpcd (Deleted in a mouse model of PCD), a gene of unknown function (Zariwala et al., 2004). Human DPCD and Pol- are expressed at high level in the testis, but only DPCD expression is increased during ciliated cell differentiation (Zariwala et al., 2004).
About half of the Pol-–/–/Dpcd–/– mice die by 3 weeks of age and about 70% die by 9 weeks. The sensitivity to DNA-damaging agents is not affected, suggesting that another DNA polymerase compensates for the deficiency of Pol- in BER processes. Five of 26 Pol-–/–/Dpcd–/– embryos have a situs inversus totalis. Pol-–/–/Dpcd–/– mice develop hydrocephalus and growth retardation by 2–4 weeks of age, as well as chronic suppurative sinusitis. Cilia of the respiratory and ependymal cells are lacking the axonemal IDAs. Pol-–/–/Dpcd–/– males are sterile, and epididymal spermatozoa are immotile with truncated or short tails and abnormally shaped heads (no ultrastructural data). Microinjection of Pol-–/–/Dpcd–/– spermatozoa into oocytes gives rise to normal offspring, suggesting that the meiotic recombination process and DNA repair are normal in Pol-–/–/Dpcd–/– mice (Kobayashi et al., 2002). Other mice were found to be normal after deletion of only the catalytic domain of Pol- (Bertocci et al., 2002). Taken together, it was concluded that at least the PCD phenotype of Pol-–/–/Dpcd–/– mice is most likely due to the loss of Dpcd (Zariwala et al., 2004).
Type 1 lissencephaly is a human autosomal-dominant congenital disorder, characterized by a smooth surface of the brain because of abnormal neuronal migration during early development. Until now, mutations in four genes have been found to be associated with distinct type 1 lissencephaly syndromes. Among these genes is lissencephaly 1 (LIS1) (Forman et al., 2005). Mice with one inactive Lis1 allele also display disorganization of the brain cortex, hippocampus and the olfactory bulb, whereas homozygous Lis1 null mice die during early embryogenesis (Hirotsune et al., 1998).
The official symbol for the Lis1 gene is Pafah1b1 (platelet-activating factor acetylhydrolase, isoform 1b, ß-1 subunit) and Lis/Pafah1b1 inactivates platelet-activating factor (Paf). The intracellular type I paf-ah is a G-protein-like complex with an 
1-subunit reminiscent of a small GTPase, like p21 ras, and Lis1 is the homologue of the ß-subunit (Ho et al., 1997). Paf-ah1b is expressed in developing brain structures and in the testis (Koizumi et al., 2003). In the mouse, the association of Lis1/Pafah1b1 with nuclear distribution C (NUDC) and mNudE-L suggests a role in dynein-mediated nuclear migration (Sweeney et al., 2001). Moreover, NudE-L has been found to play a role in the dynein-mediated transport of Lis1 to the centriole in HeLa cells (Guo et al., 2006). The 2.3-kbp Lis1 transcript is expressed in mouse germ cells, most likely in spermatids, where Lis1/Pafah1b1 partially co-localizes with dynein and tubulin and the microtubular manchette but not with the axoneme. Paf has been implicated in sperm motility (Roudebush, 2001), acrosome function (Benoff, 1998) and pathogenesis of testicular ischemia (Palmer et al., 1997).
Mouse Lis1GT/GT mutant was obtained by gene trap integration to selectively disrupt the testis Lis1 splicing variant. Homozygous mutant males are infertile with a blockage of late spermatid differentiation and severe germ cell apoptosis. Very few spermatozoa are present in small clusters, and frequently abnormal spermatids appear mostly round rather than elongated. Lis1GT/GT spermatids develop multiple acrosomal vesicles or dilated acrosomes containing two distinct vesicles with proacrosomal granules. The chromatin is poorly condensed, and the nucleus presents numerous invaginations and kinks. In many spermatids, the centrioles are normally implanted on the nucleus through the connective piece but fail to form an axoneme, whereas some spermatids have several flagella-like protrusions (Nayernia et al., 2003).
Rosa 22 male mice are sterile because of a recessive gene trap mutation of GTRGEO22, now known to correspond to PGs1, a subunit of the tubulin polyglutamylase (Regnard et al., 2003). PGs1 is implicated in the localization of the enzyme at sites of polyglutamylation on tubulin. PGs1 contains a sequence that exhibits homology to the Cyclic adenosine 5"-monophosphate (c-AMP)-dependent protein kinase (PKA) anchoring protein (AKAP)-binding domain. There is a strong concentration of PGs1 in the proximal part of the mouse sperm flagella (Regnard et al., 2003).
ROSA22 homozygote males display normal mating behaviour but are deficient in inter-male aggression (Campbell et al., 2002). They also have a lower body fat content. Ciliated epithelial cells contain normal axonemes. Rosa22 male mice are sterile. In spermatids, the axonemal anomalies extend progressively. Missing doublets or central microtubules or total axonemal disorganization is first seen in 50% of steps 2–3 spermatids, then in almost all spermatids at step 5. By steps 9–11, the flagella contain disorganized microtubule-related structures, and some spermatids have a truncated axoneme with bent microtubules poorly connected to the distal centriole. Flagella structures detach from the heads in late spermatids (steps 12–16) and are scattered in a cytoplasmic mass. Finally, the sperm heads are released without a flagellum (Campbell et al., 2002).
PKAs are maintained by AKAPs in subcellular domains, where they phosphorylate proteins. The major component of the mouse sperm FS is AKAP4. AKAPs and their interacting proteins in the mammalian flagella have been reviewed (Moss and Gerton, 2001; Eddy et al., 2003). AKAPs form complexes with other components of the signal-transduction pathways. AKAP4 binds to AKAP3, and AKAP3 interacts with ropporin. Ropporin interacts with the Rho-signalling pathway (Fujita et al., 2000). Rho is a small GTPase involved in the reorganization of the actin cytoskeleton. Rhophilin is a putative target for Rho, and both ropporin and rhophilin are present in the FS (Fujita et al., 2000). The FS-interacting proteins FSIP1 and FSIP2 bind to AKAP4 (Brown et al., 2003), and the sperm protein 17 binds to AKAP3 with a C-terminal Ca++/calmodulin-binding domain (Lea et al., 2004).
Akap4 null mice are infertile, and their spermatozoa have no progressive motility. Akap4–/– flagella are short, and the tip is sometimes curled or splayed apart into fine filaments (Miki et al., 2002). The assembly of the initial frameworks of the longitudinal columns and ribs of the FS is normal, but thereafter, FS proteins do not deposit on these frameworks. These data suggested that AKAP4 associates with a pre-existing template to complete the FS assembly. Proteins usually associated with the FS are absent or rare. GAPDS KO mice can be mentioned here for their discrete anomaly of the spacing of the FS ribs (Miki et al., 2004). GAPDS is the spermatogenic cell-specific glycolytic enzyme glyceraldehydes 3-phosphate dehydrogenase (Eddy et al., 2003).
The mouse autosomal Ube2b gene is highly homologous to Rad6 in Saccharomyces cerevisiae, which encodes an ubiquitin-conjugating enzyme (EB2 enzyme). Ube2b null male mice are found to be sterile, presenting with extensive apoptosis of the germ cells and testis depletion. In Ube2b–/– pachytene spermatocytes, the synaptonemal complexes are found to be longer, synaptonemal complex proteins from nearby telomeric regions are depleted and the crossing-over frequency is increased (Baarends et al., 2003). Ube2b–/–spermatozoa present a misshaped sperm head, suggesting that the major impairment of spermatogenesis in Ube2b null mice occurs during condensation of the spermatid nucleus. Ube2b null sperm flagella have an irregular flagellar diameter and impaired motility (Roest et al., 1996). At the ultrastructural level, the longitudinal columns of the FS are mislocated (Escalier et al., 2003), which is reminiscent of a human sperm phenotype (Escalier, 2003).
Nectins are Ca2+-independent immunoglobulin-like cell–cell adhesion molecules. Nectins play an important role in the formation of many types of cell–cell junctions and cell–cell contacts, including cadherin-based adherens junctions (AJs) and synapses. Nectins induce activation of both Cdc42 and Rac small G proteins, which eventually enhances the formation of cadherin-based AJs through the reorganization of the actin cytoskeleton (Irie et al., 2004). Nectin-2 is linked to F-actin by the actin filament-binding protein called l-afadin (Takai and Nakanishi, 2003; Takai et al., 2003). Nectin-2 expression is ubiquitous, and it is found in the testes only during the later stages of spermatogenesis. In spermatids, nectin-2 is expressed on the plasma membrane, predominantly in the middle piece.
Nectin-2–/– male mice are infertile and produce abnormal spermatozoa (Bouchard et al., 2000). Sperm nuclei are irregularly shaped with indentations. The tightly packed helical sheath of mitochondria fails to assemble, and mitochondria are frequently present alongside the nucleus with the other flagellar structures. Contrary to wild-type spermatozoa, F-actin is mainly present in the head, with less in the middle piece, in nectin-2–/– mice. It was suggested that nectin-2 is required in the middle piece for proper localization of F-actin, through the interaction with l-afadin. Nectin-2 might bring the l-afadin–F-actin complex to the middle piece and mediate structural changes of actin (Bouchard et al., 2000).
Septins (Sept) are polymerizing GTP-binding proteins required for cell cortical organization during cytokinesis. In mammalian cells, septins have been implicated in the completion of cytokinesis, vesicle trafficking and cytoskeletal filament formation (Spiliotis and Nelson, 2006). A splice variant derived from the septin 4 locus is a pro-apoptotic septin termed ARTS (apoptosis-related protein in the transforming growth factor-signalling pathway) that localizes to the mitochondria. SEPT1/4/6/7 form the major structural basis of the mammalian sperm annulus (Ihara et al., 2005). Septin 4 is expressed in post-meiotic male germ cells.
In one mouse model (Kissel et al., 2005), the Sept4 locus was eliminated. This locus contains Sept4/H5, Sept4/apCdcrel-2b and Sept4/M. Sept4 locus null spermatozoa are immotile in the cauda epididymis, lose the capacitation potential and 50–70% of them display a 180° tail bending (not seen in spermatozoa from the testis and caput epididymis). The tail diameter appears thinner at the level of the midpiece–principal piece junction. The annulus is totally absent, and small mitochondria are stacked between mitochondria of normal size. The mitochondria are metabolically active but contain fewer cristae. The cytoplasmic droplet does not migrate towards the annulus, after the bulk cytoplasm is removed. Heterozygote mice are fertile with motile spermatozoa, and 20–30% of their flagella exhibit an L-shape.
In the second mouse model, the entire coding Sept4 exons 2 to 10 are replaced with a neo cassette to make a null allele (Ihara et al., 2005). Spermatozoa are either completely immotile or exhibit abnormal flagellar movement. Sept4 null spermatozoa are viable and able to generate ATP but contain an excess of ATP reserve, indicating that the major ATPases, such as dyneins, cannot utilize ATP. The annulus is replaced by a fragile segment lacking the annulus. The flagella internal structures are broken when spermatozoa start moving in the cauda epididymis. In Sept4 null spermatozoa, SEPT1, 6 and 7 are delocalized and dispersed throughout the cytoplasm, and kinesins accumulate near the midpiece–principal piece junction. Fertility can be obtained by ICSI.
Selenoprotein P (Sepp1) is the major transporter of selenium in the serum, and it maintains brain selenium levels (Burk and Hill, 2005). In the testis, Sepp1 mRNAs are expressed in Leydig cells and spermatids. In germ cells, the selenium is incorporated into the selenoprotein called phospholipid hydroperoxide glutathione peroxidase (PHGPx). PHGPx co-localizes with sperm mitochondria-associated cysteine-rich protein (smcp) in the sperm middle piece (Nayernia et al., 2004). In the seminiferous tubules, only the Sertoli cells and the spermatogonia are exposed to interstitial fluid and may play a role in Sepp1 binding.
Complete Sepp1 KO mice develop neurological deficiencies (Richardson, 2005), and males present sharply reduced fertility and a low selenium level in the testis (Hill et al., 2003; Schomburg et al., 2003). Sepp1–/– males develop flagellar structural defects during spermiogenesis and in the epididymis (Olson et al., 2005). Caput epididymis spermatozoa of Sepp1–/– males display a hairpin-like flagellar bend at the midpiece–principal piece junction within a common plasma membrane. The mitochondrial sheath does not reach the annulus. The outer dense fibres and axonemal microtubules of the principal piece are fractured, leading to extrusion of axonemal doublets no. 4–7 and their associated outer dense fibres. These extruded structures are seen between the mitochondrial sheath and plasma membrane. In the cauda epididymis, most of Sepp1–/– flagella have a sharp hairpin configuration and occasionally are coiled or kinked at the head–tail and/or midpiece–principal piece junctions. Spermatozoa with hairpin flagella frequently display weak beating. The mitochondria appear pale, swollen and lack the typical internal structural organization. The sperm defects found in Sepp1–/– males appear to be the same as those observed in Sepp1+/+ males fed on a low selenium diet. Feeding supplemental dietary selenium to Sepp1–/– males does not reverse infertility or prevent the development of defective spermatozoa, indicating that Sepp1 plays an obligatory role in flagella morphogenesis. It is worth noting that mice deficient in the mitochondria-associated cysteine-rich protein have sperm motility disorders without anomalies of the sperm flagella (Nayernia et al., 2002).
Golgi-associated postsynaptic density-95/Discs large/zona occludens-1 (PDZ) and coiled-coil motif containing (Gopc) is a Golgi-associated protein (also known as Pist, Gal or Fig) that interacts with golgin-160 and somatostatin receptor subtype 5 and could be involved in Golgi structure and function and in plasma membrane proteins and vesicular trafficking (Hicks and Machamer, 2005; Wente et al., 2005). Gopc binds to TC-10, a member of the Rho-GTPase family involved in the regulation of the endocytic pathway (Neudauer et al., 2001). In the mouse, Gopc is located in the perinuclear region in spermatocytes and in the cytoplasmic compartment in elongated spermatids. In round spermatids, Gopc is located in the region between the Golgi stacks and the developing acrosomal cap.
Male Gopc–/– mice are infertile (Yao et al., 2002). Spermatozoa motility is reduced, both in the number of motile cells and in velocity. The sperm nucleus in Gopc–/– mice is round or ovoid, and the acrosome is either absent or fragmented and not associated with the nucleus. The primary defect is a defective fusion of the Golgi-derived transport vesicles to the acrosomal cap. An abnormally high number of mitochondria accumulate in several layers, impairing the development of a typical helical mitochondrial sheath (Toshimori et al., 2004). The flagella are coiled around the nucleus and dislocated from the implantation fossa. The absence of the perinuclear ring (Ito et al., 2004) should be responsible for the loss of flagella integrity in the cauda epididymis (Suzuki-Toyota et al., 2004).
Keratin 9 (Krtl1–9) is one of the components of the perinuclear ring of the spermatid manchette (Kierszenbaum, 2002). The insertion of the neor gene into intron 6 of keratin 9 results in the expression of both wild-type K9 and a truncated K9 protein (Rivkin et al., 2005). All mutant mice are fertile. In K9+/neo and K9neo/neo male mice, 35% of the spermatids have an ectopic manchette. Maturing spermatids exhibit coiled tails, and about 40% of the epididymal K9+/neo and K9neo/neo spermatozoa have hooked and U-shaped tails, shortened and thick tail, and some are conjoined sperm with hooked tails, fused distally. A residual cytoplasm is found at the end of the mitochondria-containing middle piece and adjacent to the annulus. U-shaped epididymal sperm exhibit forward motility and axial rotation even with an inverted orientation of the bent heads. Myosin Va is found to accumulate in the residual cytoplasmic region. In offspring derived from ICSI using K9neo/neo sperm, about 76% have similar sperm anomalies, in terms of frequency and morphology, to those found in K9neo/neo mutant males. 90% of F1 progeny lack heterozygosity; these mice do not have the neor gene inserted in the K9 gene and appear to have a wild-type genotype.
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Other factors possibly involved in sperm flagellum assembly |
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TOPAbstractIntroductionTargeted factors in KO...Other factors possibly involved...ConclusionReferences |
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IFT88/Tg737
In mammals, IFT particle proteins are expressed in the testis, suggesting that they could be involved in the assembly of motile sperm flagella (Baker et al., 2003) and that a mutation in an IFT particle protein could lead to sperm with short, disorganized tails (Pazour et al., 2006).
Flagella are absent in Chlamydomonas lacking the IFT88 particle subunit. IFT88 is homologous to the mouse and human Tg737 genes. Tg737D2–3bGal mice have a random left-right axis determination and die during early to mid-gestation (Moyer et al., 1994). Hypomorphic Tg737orpk mice survive into young adulthood and exhibit cystic kidneys, liver and pancreatic defects, skeletal patterning anomalies and lack node cilia (Murcia et al., 2000). Primary cilia in the kidney of Tg737orpk mutant mice are shorter than normal (Pazour et al., 2000). In the mouse, Tg737 encodes Polaris, which is expressed in cilia from lungs, efferent ducts and sperm flagella (Taulman et al., 2001). This suggests that Polaris could be involved in assembly of mammalian flagella, but the sperm phenotype of Tg737orpk has not been reported. It is worthy to note that Drosophila mutants lacking a homologue of IFT88 have defective sensory cilia but normal sperm (Han et al., 2003). Conversely, silencing IFT88 by RNA interference impairs the assembly of a flagellum in Trypanosoma (Kohl et al., 2003). A mitogen-activated protein kinase has been found to be involved in the elongation and maintenance of the flagellar axoneme in Leishmania (Erdmann et al., 2006). An absence of flagellum biogenesis is also seen in Trypanosoma after silencing the dynein heavy-chain Dnahc1b gene (Kohl et al., 2003).
Finally, preliminary data have been published on mice deficient in the centrosomal protein speriolin (Spatc1) (Goto and Eddy, 2004). Spatc1–/– mice have a reduced fertility. Spatc1–/– spermatozoa present ultrastructural defects in the centrosomal region and are easily decapitated by treatment with low concentrations of detergents. Eggs fertilized with Spatc1–/– spermatozoa give rise to abnormal zygotes that often have two nuclei, fail to extrude the secondary polar body and lack a bipolar spindle (M Goto et al.; Biol Reprod., special issue, 2005, W318, p152).
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Conclusion |
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TOPAbstractIntroductionTargeted factors in KO...Other factors possibly involved...ConclusionReferences |
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Data from KO mice continue to enrich our knowledge of male infertility and demonstrate the efficacy of loss-of-function studies to identify new genes required for mammalian sperm flagella assembly. Molecular biology and genetics have widely contributed to the production of these KO mice, and recently, significant progress has been made in the identification of factors specific to unique structures of the mammalian flagellum (Eddy et al., 2003
; Inaba, 2003). Also, analysis of the murine genome has revealed the conservation of many axonemal genes throughout evolution. Finally, the growing number of Chlamydomonas reinhardtii mutants with axonemal anomalies has contributed to the identification of genes involved in axonemal assembly.
Table II shows that several of these KO mice presented variable phenotypes. Genetically altered mice derived by homologous recombination in 129 embryonic stem cell (ES) lines may exhibit highly variable phenotypes because of variation in genetic background, indicating that genes unrelated to the targeted genes can markedly affect the observed phenotype. Backcross breeding diminishes overall genetic heterogeneity, but selection for the targeted locus maintains flanking parental genomic DNA, precluding generation of identical congenic experimental and control mice (Erdmann et al., 2006). ES KOs imply some other inherent limitations that have been presented elsewhere. Considerations included confounding effects because of the promoter used, position-effect variegation and insertion of tandem multi-copy arrays (Escalier, 1999, 2001). RNA interference is now used in mammals, which could minimize the undesired position effects. However, among the several causes of variable phenotypes for Mendelian traits are alternative alleles, environmental factors and modifier genes that affect penetrance (Nadeau, 2001). The role of ligand–receptor interactions, intra- and intercellular signalling, chaperones and the protein degradation and apoptotic pathways, and many other processes are all potential mediators of phenotypic modifications (Nadeau, 2001).
Of the 23 mouse models presented here, 22 are sterile in the homozygous state, but heterozygous animals are fertile and have normal sperm flagella in most cases. This is probably also the case in humans, because most of specific sperm flagellar anomalies are found in consanguineous patients (Baccetti et al., 2001). An interesting finding is that the male sterility is rescued in five of six of the mutant mice by the ICSI procedure. Cases of human male infertility where spermatozoa bear defects which probably have a genetic basis can also be rescued by ICSI (Peeraer et al., 2004). Murine and human amino acid sequences of flagellum genes are often highly homologous (Li et al., 2004), which is promising for the genetic investigation of cases of human male infertility with specific flagellar anomalies phenotypically comparable with a KO mouse model. In humans, at least 14 different abnormal flagellar phenotypes could have a genetic basis, as indicated by their occurrence in family cases and/or in men with consanguinity (unpublished data). Mouse models for some of these rare human sperm phenotypes are now available. The recent acceleration of the production of mice with sperm flagellum anomalies is very promising and will provide many candidate genes for genetic analysis in humans in few years. However, data show that different genes affecting the assembly of the axoneme could lead to apparently similar phenotypes. Therefore, to define the best candidate gene for a given human sperm flagellar syndrome, only precise ultrastructural analysis of the spermatozoa can allow comparisons between flagellar structure disorders in humans and KO mice. Moreover, the molecular mechanisms that contribute to the building of axonemal and peri-axonemal structures remain poorly understood. This could be explained by the fact that the functions of the factors involved in most of the KO mice described here have to be refined. These studies will accelerate efforts to translate newfound knowledge of the human and mouse genomes into better strategies for diagnosing human male infertility. Such knowledge could raise the possibility of future treatment for cases where a simple genetic disorder is involved.
In conclusion, determining the genetic basis for abnormal flagella phenotypes and the genes that underlie human male infertility greatly depends on developing models, by targeting mutagenesis, as well as further advances in molecular biology.
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Acknowledgements |
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I thank Dr E. Broneer for reviewing the text in English and anonymous reviewers for their useful critical comments. This work was supported by funds from the Institute of Rare Diseases (INSERM, GIS 0334, Paris, France). I apologize to those investigators whose work was not cited, or cited only through reviews, because of the brevity of this review.
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