Zygotene cilia regulate meiosis, germ cell development and fertility in zebrafish, mice, and humans

Germ cells accurately organize their chromosomes through the program of meiosis to successfully generate haploid gametes for fertilization1. Chromosomal pairing, which is essential for homologous recombination, is controlled by the cytoskeletal machinery of perinuclear microtubules that are organized by the centrosome2–4, but the underlying biomechanical regulation has remained incompletely understood. We have recently discovered the zygotene cilium in zebrafish oocytes, which mechanically anchors the centrosomal centrioles to facilitate chromosomal pairing dynamics and is essential for female meiosis5. Here, we show that cilia also regulate chromosomal dynamics and testis morphogenesis in the zebrafish male germline. Importantly, using germ cell-specific conditional elimination of zygotene cilia in mice, we establish a previously unrecognized ciliary function in chromosomal synapsis, germ cell development and fertility in mammals. Furthermore, we document the occurrence of cilia in human meiotic germ cells by identifying ciliary structures as well as gene expression signature of ciliary differentiation through single-cell transcriptomics. Finally, we have identified high impact variants in ciliary genes in women with premature ovarian insufficiency (POI) and men with crypto-/azoospermia, indicating that zygotene cilia defects may underlie their reproductive failure. Together, our findings uncover a strikingly conserved ciliary mechanism in the regulation of chromosomal dynamics in meiosis and implicate dysfunction of the zygotene cilium as an overlooked aetiology of human infertility.