Identification of the molecule that regulates sperm motility (Ikawa Lab, in PNAS)

Sperm motility is essential for sperm to traverse the female reproductive tract to deliver half of the male’s genome to the oocyte. Sperm with reduced motility or immotile sperm, a condition referred to asthenozoospermia, leads to infertility in men. Among all infertile men, 18% present with asthenozoospermia. Sperm motility is dependent on the formation and functioning of the flagellum, a whip-like appendage used for locomotion. The principal components of the flagellum are the axoneme, which comprises the “9+2” microtubule arrangement, dynein arms, radial spokes, and the Nexin-Dynein Regulatory Complex (N-DRC). Failure to properly assemble any of these components lead to sperm with decreased motility or non-motile sperm. T-Complex-Associated-Testis-Expressed 1 (TCTE1) is an evolutionarily conserved axonemal protein present from Chlamydomonas (DRC5) to mammals that localizes to the N-DRC. Here, we show that mouse TCTE1 is testis-enriched in its expression, with its mRNA appearing in early round spermatids, and protein localized to the flagellum. TCTE1 is 498 amino-acids in length with a Leucine Rich Repeat domain at the C-terminus and is present in eukaryotes containing a flagellum. Knockout of Tcte1 results in male sterility because Tcte1 null spermatozoa show aberrant motility. Although the axoneme is structurally normal in Tcte1 mutant spermatozoa, Tcte1 null sperm demonstrate a significant decrease of ATP, which is utilized by dynein motors to generate the bending force of the flagellum. This work provides a link in defining the molecular intricacies required for axoneme function, sperm motility, and male fertility.

This research project was conducted in collaboration with Baylor College of Medicine and Nanjing Medical University.

Upper Fig.: TCTE1 is a component of DRC (nexin-dynein regulatory complex)

Lower Fig.: Electron micrographs for sperm flagella

This article is published in PNAS (online) on June 19 2017.

TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa

PNAS 2017 ; Jul 3;114(27):E5370-E5378., doi:10.1073/pnas.1621279114