Building functional sperm

Many thousands of genes are required for male fertility in mammals. In the testis, these genes govern the diverse individual processes of mitosis, meiosis and spermiogenesis, which are ultimately required to generate sperm. During this latter process of spermiogenesis, round spermatids undergo a complete remodelling to generate a sperm tail for motility, sculpt the nucleus into species-specific head shape and acquire additional structures required for fertility, such as the acrosome (Pleuger et al., 2020). In recent years, and through the harnessing of next generation sequencing, the field has discovered a significant number of genes important for sperm tail development (Nsota Mbango et al., 2019; Toure et al., 2021). However, we are far from understanding the full picture.

In a recent study, Tan et al. (2022) has identified yet another gene required for the normal formation of the sperm tail:  DNHD1 (Dynein Heavy Chain Domain 1). The authors performed exome sequencing on 497 unrelated men suffering from asthenoteratozoospermia – the production of sperm with abnormal morphology and impaired motility – and found a whopping 14 unique genetic variants in DNHD1 across eight men (Tan et al., 2022). Two of these men were homozygous for the same variant, while the remaining six men presented with compound heterozygous variants, and all were predicted to be pathogenic. As is a common consequence of impaired tail development, DNHD1 dysfunction in these men resulted in sperm with coiled and short tails and the coincident impairment of sperm motility. Tan and colleagues next made a knockout mouse to recapitulate the effect of loss of function DNHD1 genetic variants on male fertility. The absence of Dnhd1 in mice resulted in the same phenotype as seen in men – infertility due to asthenoteratozoospermia, confirming the conserved and essential role of DNHD1 in mammalian male fertility.

The authors hypothesise that DNHD1 functions in the process of intraflagellar transport, whereby proteins and vesicles are shuttled along the developing sperm tail for their incorporation (Tan et al., 2022). Intraflagellar transport is driven by molecular motors – kinesin and cytoplasmic dynein 2  (Pleuger et al., 2020) – thus it is conceivable how DNHD1, a dynein protein, may act in this process. Though we are far from deciphering the entire cohort of genes required for spermiogenesis and its sub-processes, studies like this continue to improve our understanding of the molecular mechanisms required to generate the rockets of the reproductive world.

Nsota Mbango, J. F., Coutton, C., Arnoult, C., Ray, P. F. and Toure, A. (2019). Genetic causes of male infertility: snapshot on morphological abnormalities of the sperm flagellum. Basic Clin Androl 29, 2.

Pleuger, C., Lehti, M. S., Dunleavy, J. E., Fietz, D. and O’Bryan, M. K. (2020). Haploid male germ cells-the Grand Central Station of protein transport. Hum Reprod Update.

Tan, C., Meng, L., Lv, M., He, X., Sha, Y., Tang, D., Tan, Y., Hu, T., He, W., Tu, C. et al. (2022). Bi-allelic variants in DNHD1 cause flagellar axoneme defects and asthenoteratozoospermia in humans and mice. Am J Hum Genet 109, 157-171.

Toure, A., Martinez, G., Kherraf, Z. E., Cazin, C., Beurois, J., Arnoult, C., Ray, P. F. and Coutton, C. (2021). The genetic architecture of morphological abnormalities of the sperm tail. Hum Genet 140, 21-42.

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