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Sperm Guidance in Mammals — an Unpaved Road to the Egg

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Sperm Guidance in Mammals — an Unpaved Road to the Egg REVIEWS Sperm guidance in mammals — an unpaved road to the egg Michael Eisenbach* and Laura C. Giojalas‡ Abstract | Contrary to the prevalent view, there seems to be no competition in the mammalian female genital tract among large numbers of sperm cells that are racing towards the egg. Instead, small numbers of the ejaculated sperm cells enter the Fallopian tube, and these few must be guided to make the remaining long, obstructed way to the egg. Here, we review the mechanisms by which mammalian sperm cells are guided to the egg. Capacitation For fertilization to occur in mammals, ejaculated sper ma- — the directed movement of cells along a temperature A ripening process that tozoa must reach the egg, which, following ovulation, gradient. spermatozoa must undergo in has moved from the ovary into the Fallopian tube. Until Chemotaxis was discovered as a form of sperm guid- order to penetrate the female’s not too long ago, the common belief was that, in mam- ance in the mid-1960s in marine species9,10, and has egg and fertilize it. mals, following ejaculation into the female genital tract, only been recognized in amphibians and mammals in 7,11 Acrosome reaction large numbers of spermatozoa ‘race’ towards the egg and the past 15 years . The initial resistance to the notion The release of proteolytic compete to fertilize it. This dogma, as well as conflicting of sperm chemotaxis in mammals was compounded by enzymes from the top part results in the literature, instilled the idea that the guid- the inconsistent conclusions drawn from initial studies of the sperm’s head, known as ance of sperm to the egg was superfluous in mammals. (see REFS 3,11 for reviews). One of the main reasons for the acrosome, which enables sperm penetration through the The ‘competitive-race model’ dismantled when it became the apparent inconsistency was the very low signal-to- egg coat. clear that, in fact, few of the ejaculated spermatozoa (in noise ratio that was obtained in chemotaxis assays with humans, only ~1 of every million spermatozoa) succeed mammalian spermatozoa. This factor, combined with Chemotaxis in entering the Fallopian tubes1–3. Furthermore, the suboptimal experimental conditions and a failure to The movement of cells in the number of spermatozoa that can fertilize the egg is even distinguish between true chemotaxis and other causes direction of a chemoattractant gradient. smaller. Spermatozoa must undergo a process of ripening, of sperm accumulation (reviewed in REF. 3), resulted in known as capacitation, and only capacitated spermatozoa conflicting results and ambiguity. Today, we know that Chemoattractant can penetrate the cumulus layer that surrounds the egg, the low signal-to-noise ratio is caused by the fact that, in A factor (a peptide or any bind to the sperm receptor on the egg coat, and undergo mammals (unlike sperm chemotaxis in marine species9), other chemical) that attracts acrosome reaction specific cells by chemotaxis. the that enables sperm penetration only the small fraction of capacitated spermatozoa are through the egg coat and then fusion with the egg (see chemotactically responsive5,12–14. This realization, com- Thermotaxis REF. 4 for a review). bined with the development of assays that allow chemo- The movement of cells that is The percentage of capacitated spermatozoa is low (~10% taxis to be distinguished from other processes7 (BOX 1), directed according to a in humans)4–6 and, therefore, the number of sperm atozoa has established that chemotaxis is indeed a mammalian temperature gradient. that can reach and fertilize the egg is small. The chances that sperm-guidance mechanism. such low numbers of spermatozoa will successfully reach The first experiments in mammals showed that human follicular fluid15,16 *Department of Biological the egg by coincidence, without a guidance mechanism, sperm accumulated in the , and that there Chemistry, the Weizmann are very slim. This realization has fuelled an interest in was a remarkable correlation between this in vitro accum- Institute of Science, 76100 the study of sperm guidance in mammals, and here we ulation and egg fertilization16. Subsequent experiments Rehovot, Israel. summarize the state of the art in this young and rapidly confirmed that this accumulation was indeed the con- ‡ Center for Cell and Molecular changing field, comment on new findings and discuss the sequence of chemotaxis17. Sperm chemotaxis was later Biology, Faculty of Sciences, 18 14,19 13 National University of direction in which this research will probably go. also demonstrated in frogs , mice and rabbits . In Córdoba, Avenue Vélez addition, the accumulation of sperm in follicular fluid Sársfield 1601, Mechanisms of mammalian sperm guidance (but without substantiating that it truly reflects chemo- 5000, Córdoba, Argentina. Two active mechanisms of sperm guidance have been taxis) was demonstrated in horses20 and pigs21. So, sperm Correspondence to M.E. chemotaxis e-mail: shown in mammals: , which is the movement chemotaxis seems to be a widespread mechanism that [email protected] of cells up a concentration gradient of chemoattractant guides spermatozoa to the egg, both when fertilization is doi:10.1038/nrm1893 (see REF. 7 for an extensive review), and thermotaxis8 external (as in marine species) or internal. 276 | APRIL 2006 | VOLUME 7 www.nature.com/reviews/molcellbio REVIEWS 5 Box 1 | The measurement of sperm chemotaxis that reach the storage site, only some become capacitated . These few spermatozoa have to negotiate the long (2–6 cm In sperm chemotaxis assays, it is essential to apply well-defined criteria that distinguish in humans1,23 and ~10 cm in rabbits24) obstructed road between chemotaxis and other processes that might cause sperm accumulation. that separates them from the egg at the fertilization site25. There are two main criteria: the directional change of sperm movement towards the In vitro findings indicate that capacitated spermatozoa chemoattractant source — a unique feature of chemotaxis, which, unfortunately, is fulfilled in only the first two assays that are commonly used to measure sperm are guided from the storage site to the egg primarily by a 5,26 8 chemotaxis (see below), and a peak-like dependence (rather than a saturation-curve combination of chemotaxis and thermotaxis , assisted 27 dependence) of the measured response on the chemoattractant concentration. perhaps by oviductal contractions . The latter criterion applies to all chemotaxis assays and it relies on the fact that when a It would seem logical that the capacitated spermatozoa certain chemoattractant concentration saturates its cognate receptor, the cell cannot at the storage site use an ovulation-dependent temperature sense any further increases in the chemoattractant concentration and, as a result, the gradient between this site and the fertilization site24,28,29 as chemotactic response drops. a ‘road sign’ to guide them to the site of fertilization by The assays listed below have been used to determine sperm chemotaxis. In all of them, thermotaxis. Additionally, the finding that, at least in mice, a comparison is made to a no-gradient situation as a control. oviductal fluid contains one or more chemo attractants14 Directionality assays raises the possibility that different chemoattractants might The video-recorded movement tracks of spermatozoa in a chemoattractant gradient be secreted along the oviduct to promote sequential, are analysed to determine which tracks involve directional changes towards the source short-range chemotactic processes towards these chemo- of the chemoattractant. The gradient can be two-dimensional (when the source is attractants. As the spermatozoa approach the vicinity point-like)17,35,36,49 or linear (when the source is linear)13. of the fertilization site, they probably sense a chemo- Descending chemoattractant gradient assays attractant gradient that originates at the cumulus cells26 (see Spermatozoa are suspended in a solution containing a chemoattractant and below), which guides them to the egg–cumulus complex. their accumulation at the bottom of a chemoattractant gradient is compared with their However, the arrival at this complex does not guarantee accumulation at the same location when the chemoattractant concentration is 30 constant throughout the measuring unit (a no-gradient control)11,17. Chemotactically entry into the egg itself , because the egg is covered with responsive spermatozoa (unlike chemokinetically responsive spermatozoa that respond a dense matrix that is composed of hundreds of cumulus to the chemoattractant by only increasing their speed of movement) are expected to cells (FIG. 1). It is thought that a chemoattractant gradient accumulate to a lesser extent in the former setup. Trapped spermatozoa would not that originates at the egg is established within the cumulus distinguish between the presence and absence of a gradient. Therefore, in most cases, matrix, which guides the spermatozoa to the egg26. Indeed, this assay allows a distinction between chemotaxis, chemokinesis and trapping. the first few spermatozoa that enter the cumulus are Sperm accumulation in an ascending chemoattractant gradient successful in finding the egg31. The number of spermatozoa that sense an ascending chemoattractant gradient and accumulate near or at its source is counted. Because sperm accumulation can also be Mammalian sperm chemotaxis caused by trapping or changes in swimming speed, this method cannot distinguish Physiology of sperm chemotaxis. The encounter between
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