No abstract

These observations suggest that sperm chemoattractants are secreted not only prior to ovulation within the follicle, as earlier studies have demonstrated, but also after oocyte maturation outside the follicle, and that there are two chemoattractant origins: the mature oocyte and the surrounding cumulus cells.

Thermotaxis--movement directed by a temperature gradient--is a prevalent process, found from bacteria to human cells. In the case of mammalian sperm, thermotaxis appears to be an essential mechanism guiding spermatozoa, released from the cooler reservoir site, towards the warmer fertilization site. Only capacitated spermatozoa are thermotactically responsive. Thermotaxis appears to be a long-range guidance mechanism, additional to chemotaxis, which seems to be short-range and likely occurs at close proximity to the oocyte and within the cumulus mass. Both mechanisms probably have a similar function--to guide capacitated, ready-to-fertilize spermatozoa towards the oocyte. The temperature difference between the site of the sperm reservoir and the fertilization site is generated at ovulation by a temperature drop at the former. The molecular mechanism of sperm thermotaxis waits to be revealed.

On the basis of the finding that capacitated (ready to fertilize) rabbit and human spermatozoa swim towards warmer temperatures by directing their movement along a temperature gradient, sperm thermotaxis has been proposed to be one of the processes guiding these spermatozoa to the fertilization site. Although the molecular mechanism underlying sperm thermotaxis is gradually being revealed, basic questions related to this process are still open. Here, employing human spermatozoa, we addressed the questions of how wide the temperature range of thermotaxis is, whether this range includes an optimal temperature or whether spermatozoa generally prefer swimming towards warmer temperatures, whether or not they can sense and respond to descending temperature gradients, and what the minimal temperature gradient is to which they can thermotactically respond. We found that human spermatozoa can respond thermotactically within a wide temperature range (at least 29–41°C), that within this range they preferentially accumulate in warmer temperatures rather than at a single specific, preferred temperature, that they can respond to both ascending and descending temperature gradients, and that they can sense and thermotactically respond to temperature gradients as low as <0.014°C/mm. This temperature gradient is astonishingly low because it means that as a spermatozoon swims through its entire body length (46 µm) it can sense and respond to a temperature difference of <0.0006°C. The significance of this surprisingly high temperature sensitivity is discussed.

Capacitated human and rabbit spermatozoa can sense temperature differences as small as those within the oviduct of rabbits and pigs at ovulation, and they respond to them by thermotaxis (i.e., by swimming from the cooler to the warmer temperature). The molecular mechanism of sperm thermotaxis is obscure. To reveal molecular events involved in sperm thermotaxis, we took a pharmacological approach in which we examined the effect of different inhibitors and blockers on the thermotactic response of human spermatozoa. We found that reducing the intracellular, but not extracellular, Ca(2+) concentration caused remarkable inhibition of the thermotactic response. The thermotactic response was also inhibited by each of the following: La(3+), a general blocker of Ca(2+) channels; U73122, an inhibitor of phospholipase C (PLC); and 2-aminoethoxy diphenyl borate, an inhibitor of inositol 1,4,5-trisphosphate receptors (IP(3)R) and store-operated channels. Inhibitors and blockers of other channels had no effect. Likewise, saturating concentrations of the chemoattractants for the known chemotaxis receptors had no effect on the thermotactic response. The results suggest that the IP(3)R Ca(2+) channel, located on internal Ca(2+) stores, operates in sperm thermotaxis, and that the response is mediated by PLC and requires intracellular Ca(2+). They also suggest that the thermosensors for thermotaxis are not the currently known chemotaxis receptors.

Highlights d Transcription strength impacts rates of mRNA decay d Transcription dynamics modulate poly(A) tail length via m 6 A and the CCR4-Not complex d IRES elements impede transcription, provoke m 6 A, and restrict mRNA stability d Global transcription changes impact the degradation machinery to buffer mRNA levels

The temperature-difference increase within the rabbit oviduct is generated at ovulation by a reduced temperature at the sperm storage site. This temperature gradient may play a role in mammalian reproduction via sperm thermotaxis.

Highlights d Discovery of Spt5-Pol II small-molecule inhibitors (SPIs) that mimic Spt5 knockdown d SPIs relieve promoter-proximal pausing and inhibit inflammatory gene activation d SPIs inhibit mutant huntingtin gene transcription and 3 0 end processing of histone genes d Selective targeting of Spt5-Pol II activities by SPIs uncouples its different functions