Sperm guidance

This was due to the common belief that, following ejaculation into the female genital tract, large numbers of spermatozoa 'race' towards the oocyte and compete to fertilize it.

So far, most sperm chemoattractants that have been identified in non-mammalian species are peptides or low-molecular-weight proteins (1–20 kDa), which are heat stable and sensitive to proteases.

Likewise, in plants, a unique simple compound [e.g., fucoserratene — a linear, unsaturated alkene (1,3-trans 5-cis-octatriene)] might be a chemoattractant for various species.

In some species (for example, in hydroids like Campanularia or tunicate like Ciona), the swimming direction of the spermatozoa changes abruptly towards the chemoattractant source.

In others (for example, in sea urchin, hydromedusa, fern, or fish such as Japanese bitterlings), the approach to the chemoattractant source is indirect and the movement is by repetitive loops of small radii.

[2][3][25][26] In chemotaxis, cells may either sense a temporal gradient of the chemoattractant, comparing the occupancy of its receptors at different time points (as do bacteria[27]), or they may detect a spatial gradient, comparing the occupancy of receptors at different locations along the cell (as do leukocytes[28]).

In the best-studied species, sea urchin, the spermatozoa sense a temporal gradient and respond to it with a transient increase in flagellar asymmetry.

The current knowledge is mainly based on studies in the sea urchin Arbacia punctulata, where binding of the chemoattractant resact (Table 1) to its receptor, a guanylyl cyclase, activates cGMP synthesis (Figure 1).

Binding of a chemoattractant (ligand) to the receptor — a membrane-bound guanylyl cyclase (GC) — activates the synthesis of cGMP from GTP.

On hyperpolarization, hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels allow the influx of Na+ that leads to depolarization and thereby causes a rapid Ca2+ entry through voltage-activated Ca2+ channels (Cav), Ca2+ ions interact by unknown mechanisms with the axoneme of the flagellum and cause an increase of the asymmetry of flagellar beat and eventually a turn or bend in the swimming trajectory.

However, the discoveries of proper stimuli in the female – an ovulation-dependent temperature gradient in the oviduct,[33][34][35] post-coitus oviductal fluid flow in female mice,[10] and sperm chemoattractants secreted from the oocyte and its surrounding cumulus cells,[36] respectively – strongly suggest the mutual occurrence of these mechanisms in vivo.

[32] In addition, sperm accumulation in follicular fluid (but without substantiating that it truly reflects chemotaxis) was demonstrated in horses[39] and pigs.

[41][42] Importantly, the fraction of capacitated (and, hence, chemotactically responsive) spermatozoa is low (~10% in humans), the life span of the capacitated/chemotactic state is short (1–4 hours in humans), a spermatozoon can be at this state only once in its lifetime, and sperm individuals become capacitated/chemotactic at different time points, resulting in continuous replacement of capacitated/chemotactic cells within the sperm population, i.e., prolonged availability of capacitated cells.

[41][44] These sperm features raised the possibility that prolonging the time period, during which capacitated spermatozoa can be found in the female genital tract, is a mechanism, evolved in humans, to compensate for the lack of coordination between insemination and ovulation.

[36] It is a hydrophobic non-peptide molecule which, when secreted from the oocyte, is in complex with a carrier protein[49] Additional compounds have been shown to act as chemoattractants for mammalian spermatozoa.

[55] The subsequent findings that cumulus cells of both human and rabbit (and, probably, of other mammals as well) secrete the chemoattractant progesterone[46][47][48] is sufficient to account for the lack of specificity in the chemotactic response of mammalian spermatozoa.

This is because the establishment of a temporal gradient in the absence of spatial gradient, achieved by mixing human spermatozoa with a chemoattractant[56] or by photorelease of a chemoattractant from its caged compound,[57] results in delayed transient changes in swimming behavior that involve increased frequency of turns and hyperactivation events.

[56][57] In other words, human spermatozoa approach chemoattractants by modulating the frequency of turns and hyperactivation events, similarly to Escherichia coli bacteria.

[58] The discovery of progesterone as a chemoattractant[46][47][48] led to the identification of its receptor on the sperm surface – CatSper, a Ca2+ channel present exclusively in the tail of mammalian spermatozoa.

[62] The realization that sperm chemotaxis can guide spermatozoa for short distances only,[7] triggered a search for potential long-range guidance mechanisms.

A small fraction of the spermatozoa (at the order of ~10%), shown to be the capacitated cells, biased their swimming direction according to the gradient, moving towards the warmer temperature.

[65] This means that when human spermatozoa swim a distance that equals their body length (~46 μm) they respond to a temperature difference of <0.0006 °C!

[10] The flow, which is prolactin-triggered oviductal fluid secretion, is generated in female mice within 4 h of sexual stimulation and coitus.

At this location, the spermatozoa may be chemotactically guided to the oocyte-cumulus complex by the gradient of progesterone, secreted from the cumulus cells.

A number of observations point to the possibility that chemotaxis and thermotaxis also occur at lower parts of the female genital tract.

For example, small, gradual estrus cycle-correlated temperature increase was measured in cows from the vagina towards the uterine horns,[71] and a gradient of natriuretic peptide precursor A, shown to be a chemoattractant for mouse spermatozoa, was found, in decreasing concentration order, in the ampulla, isthmus, and uterotubal junction.

Indeed, sperm populations selected by thermotaxis were recently shown to have much higher DNA integrity and lower chromatin compaction than unselected spermatozoa and, in mice, to give rise to more and better embryos through intracytoplasmic sperm injection (ICSI), doubling the number of successful pregnancies.