A Newly Identified Cilium in Meiosis - Deciphering the Principles and Mechanisms of the Zygotene Cilium: ZygoCiliaAct

Programme(s): HORIZON.1.1 - European Research Council (ERC)

Topic(s): ERC-2022-COG - ERC CONSOLIDATOR GRANTS

Call for proposal: ERC-2022-COG

Funding Scheme: ERC - Support for frontier research (ERC)

Grant agreement ID: 101089065

Objective:

A hallmark of meiosis is chromosomal pairing, which for decades has been a major focus in the field. However, the nuclear events of meiosis occur in the cellular context of a differentiating gamete, and pairing depends on cytoplasmic counterparts, by mechanisms that are conserved from yeast to mammals. These are essential for fertility, but how cytoplasmic counterparts of chromosomal pairing are regulated has remained enigmatic. We uncovered a previously unrecognized cilium in meiosis – the zygotene cilium, in both males and females and in zebrafish and the mouse, which completes the mechanical cytoplasmic pairing machinery, and extracellularly extend between oocytes within a conserved cellular hub, called the germline cyst. We established the ground-breaking observations that the cilium is essential for chromosomal pairing, prophase progression and cyst morphogenesis, ovary development and fertility. These uncover the novel concept of a cilium as a critical player in meiosis, propose a cellular paradigm that cilia can control chromosomal dynamics, and shed new light on reproduction phenotypes in human ciliopathies.
The zygotene cilium now allows us to zoom-out from the nuclear events of prophase to the complete cellular and developmental program of meiosis. Utilizing our holistic morphological approach in-vivo, ZygoCiliaAct will ambitiously achieve this goal in three related but independent aims. We will uncover zygotene cilium functional mechanical and regulatory components (Aim 1), decipher the ciliary developmental signals that govern meiotic prophase progression and cyst morphogenesis (Aim 2), and expand our findings to investigation in testes, as well as use zebrafish as a new model to decipher mechanisms of human ciliopathic proteins (Aim 3). With ZygoCiliaAct we are finally poised to break new grounds in unraveling long-sought-after fundamental questions cell, developmental, cilia, and reproductive biology, and advance reproduction and ciliopathy medicine.