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Aquaporin3 Is a Sperm Water Channel Essential for Postcopulatory Sperm Osmoadaptation and Migration

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Aquaporin3 Is a Sperm Water Channel Essential for Postcopulatory Sperm Osmoadaptation and Migration npg AQP3 regulates postcopulatory sperm osmoadaptation Cell Research (2011) 21:922-933. 922 © 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr Aquaporin3 is a sperm water channel essential for postcopulatory sperm osmoadaptation and migration Qi Chen1, 2, *, Hongying Peng1, *, Li Lei1, 2, *, Ying Zhang1, 2, Haibin Kuang1, 2, Yujing Cao1, Qi-xian Shi3, Tonghui Ma4, Enkui Duan1 1State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; 2Graduate School of Chinese Academy of Sciences, Beijing 100049, China; 3Unit of Reproductive Physiology, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China; 4Central Research Laboratory, Bethune Second Hospital of Jilin University, 265 Ziqiang Street, Changchun 130041, China In the journey from the male to female reproductive tract, mammalian sperm experience a natural osmotic de- crease (e.g., in mouse, from ~415 mOsm in the cauda epididymis to ~310 mOsm in the uterine cavity). Sperm have evolved to utilize this hypotonic exposure for motility activation, meanwhile efficiently silence the negative impact of hypotonic cell swelling. Previous physiological and pharmacological studies have shown that ion channel-controlled water influx/efflux is actively involved in the process of sperm volume regulation; however, no specific sperm proteins have been found responsible for this rapid osmoadaptation. Here, we report that aquaporin3 (AQP3) is a sperm wa- ter channel in mice and humans. Aqp3-deficient sperm show normal motility activation in response to hypotonicity but display increased vulnerability to hypotonic cell swelling, characterized by increased tail bending after entering uterus. The sperm defect is a result of impaired sperm volume regulation and progressive cell swelling in response to physiological hypotonic stress during male-female reproductive tract transition. Time-lapse imaging revealed that the cell volume expansion begins at cytoplasmic droplet, forcing the tail to angulate and form a hairpin-like struc- ture due to mechanical membrane stretch. The tail deformation hampered sperm migration into oviduct, resulting in impaired fertilization and reduced male fertility. These data suggest AQP3 as an essential membrane pathway for sperm regulatory volume decrease (RVD) that balances the “trade-off” between sperm motility and cell swelling upon physiological hypotonicity, thereby optimizing postcopulatory sperm behavior. Keywords: aquaporin3; sperm; osmoregulation; postcopulation Cell Research (2011) 21:922-933. doi:10.1038/cr.2010.169; published online 7 December 2010 Introduction creasing lines of evidence have shown that a physiologi- cal hypotonic stress could facilitate acrosome reaction in Studies in fish indicated that environmental osmotic human sperm through calcium increase [5] and acrosome changes trigger sperm motility [1, 2]. Interestingly, in swelling [6], and is required for mouse sperm motility most mammalian species examined, the sperm journey “start-up” once released from cauda epididymis [7], sup- from the male to female reproductive tract also experi- porting the notion that a postcopulatory hypotonic stress ences a natural osmotic decrease [3, 4], implicating that is beneficial for normal sperm function. However, like an osmotic stress response upon ejaculation is evolution- a double-edged sword, the hypotonic stress could also arily conserved for normal sperm function. Indeed, in- cause potential harms to sperm function by inducing un- wanted cell swelling [8, 9]. To counteract this negative impact, mammalian sperm have acquired mechanisms to *These three authors contributed equally to this work. drive rapid transmembrane water movement for efficient Correspondence: Enkui Duan cell volume regulation [10]. Indeed, high water perme- Tel: +86-10-64807182 ability has long been found in mammalian sperm [11-13], E-mail: [email protected] Received 22 October 2010; revised 2 November 2010; accepted 3 Novem- and ion channel-controlled water influx/efflux has been ber 2010; published online 7 December 2010 shown to be involved in postcopulatory sperm volume Cell Research | Vol 21 No 6 | June 2011 Qi Chen et al. npg 923 regulation [14-16]. However, the sperm protein(s) (such male. In the present study, each male mouse with differ- as plasma membrane channels) responsible for this trait ent Aqp3 genotypes was allowed to continuously mate have not been identified. Aquaporins (AQPs), a family of with four wild-type females (each time with one female); proteins that are believed to be involved in water trans- after one successful mating (indicated by vaginal plug), port [17], have been expected as potential candidates for the male was allowed to rest for 2 days before another sperm volume regulation due to their highly specialized female was placed in. The plugged females were indi- function for water permeability [4, 10, 18]. Among the vidually caged and their pregnancy results were tracked. AQPs, AQP7 and 8 are expressed in rodent testis and By this breeding assay, we found that although the Aqp3- sperm [19, 20], but genetic deletion of these AQPs in null males could normally plug the females, the preg- mice did not show obvious defects in the sperm function nancy rate and litter size were markedly lower compared [21-23], possibly because of functional compensation by with wild-type or heterozygous males. Nearly half of the other AQP members. We previously identified that aqua- wild-type females that mated with the Aqp3-null males porin3 (AQP3) is expressed in mouse testis [24], sug- showed no signs of pregnancy, and the remaining ones gesting a potential role in male reproductive function. In displayed reduced litter size (Table 1). These results this study, we demonstrated that AQP3 is a sperm water clearly demonstrated that Aqp3 deficiency resulted in im- channel localized on the tail of mouse and human sperm. paired male fertility, strongly suggesting a crucial role of Aqp3-null sperm showed normal motility activation AQP3 in male reproduction. in response to hypotonicity, but with impaired volume regulation against hypotonic cell swelling, characterized Aqp3–/– males have normal sperm production and their by increased tail deformation due to excessive mechani- sperm show normal motility activation in response to cal membrane stretch. Our data revealed that AQP3 physiological hypotonicity functions as a key fluid regulator responsible for rapid Initial examination of major male reproductive or- sperm hypotonic osmoadaptation during the male-female gans, including testis and epididymis, revealed no ap- reproductive tract transition, thus optimizing postcopula- parent differences between wild-type and Aqp3–/– males tory sperm behavior. Besides, the defect of the Aqp3-null in gross morphology and histology, as well as sperm sperm is clinically related, because similar sperm tail count (Supplementary information, Figure S2A-S2C). deformation is commonly found in clinical patients with As endocrine defects usually result in size and histologi- male infertility/subfertility [25]. cal changes in reproductive organs, especially in seminal vesicles, these data suggest that endocrine defects are Results highly unlikely involved in the reduced fertility of Aqp3- null males, and the observed fertility decrease might be AQP3 expression in sperm due to causes after sperm leave for female reproductive AQP3 expression in mouse testis and sperm was de- tract. Upon ejaculation, mouse sperm normally expe- tected at mRNA and protein levels (Supplementary infor- rience a physiological osmotic decrease from cauda mation, Figure S1), which is in accordance with previous epididymis (~415 mOsm) to uterine cavity (~310 mOsm) report that AQP3 is expressed in mouse testis [24]. We [26], which is beneficial for sperm motility activation. To further found that AQP3 is specifically localized to the determine the initial sperm motility activation between sperm tail during late spermatogenesis and sperm storage the wild-type and Aqp3-null sperm, we released cauda in epididymis (Figure 1A-1C). High-magnification im- epididymal sperm directly into NaCl solution with dif- munofluorescence and immunogold electron microscopic ferent osmolarities and the sperm motility was assessed analyses of isolated sperm from cauda epididymis further by Computer-Assisted Sperm Analyzer (CASA). As demonstrated that the localization of AQP3 was confined shown in Supplementary information, Figure S3A-S3E, to the principal piece of the sperm tail membrane (Figure both the genotypes of the sperm displayed lower-motility 1D-1G). In addition, immunofluorescence staining of parameters in a relatively high osmolarity (440 mOsm) AQP3 in ejaculated human sperm also showed highly similar to the male reproductive tract, while in a relative specific expression at the principal piece of the sperm tail hypotonic environment (300 mOsm) that mimics female (Figure 1H), consistent with the localization detected in uterine cavity, both showed robust motility activation. mouse sperm. Aqp3-deficient sperm undergo postcopulatory tail defor- Aqp3–/– male shows impaired fertility mation due to increased vulnerability to hypotonic uter- The prominent expression of AQP3 in the sperm led ine environment us to revisit the reproductive phenotype of Aqp3-null In contrast to the seemingly normal initial motility, the www.cell-research.com | Cell Research npg AQP3 regulates postcopulatory sperm osmoadaptation 924 A B C H Human sperm
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