Regulation paternaler Vererbung eines Argonaute Proteins in C. elegans

• Applicant: Professor René Ketting, Ph.D.
• Subject Area: Cell Biology ; Biochemistry ; Developmental Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 420526853

Sexual reproduction requires the formation of germ cells, a cell type dedicated to the mixing of genetic information of two individuals. To do so, germ cells undergo a specialized type of cell division, meiosis, that reduces the ploidy of the germ cell. Meiosis is also accompanied by extensive cellular differentiation, resulting in highly differentiated, mature germ cells, called gametes. Gametes of opposite sexes can subsequently fuse and generate a zygote that can grow into a new individual. As a result, the new individual has genetic information, in the form of chromosomes, from both parents. However, next to DNA, the zygote also inherits many additional cellular components that are of key importance for further development. Maternal contribution of such components can be expected to dominate paternal contribution, simply because the oocyte, the female gamete, is much bigger than sperm, the male gamete. Indeed, maternal inheritance is a well-known aspect of development in C. elegans, and many so-called ‘maternal-effect’ genes have been identified through genetic screens. However, also paternally inherited material significantly influences the zygote. For instance, obesity or undernourishment can be transmitted along the paternal linage in mice and tRNA fragments and miRNAs have been observed to be transmitted through sperm and to have functional impact. Such paternal inheritance is particularly striking, since spermatogenesis typically is associated with the extrusion of significant amounts of the cellular contents. Hence, paternal inheritance of any specific molecule likely requires a process that retains that molecule in the maturing sperm cell. In this research proposal, I describe our recent identification of a novel type of phase-separated structure, defined by the protein PEI-1. This protein is required to protect a protein named WAGO-3 from extrusion from the maturing sperm cell, and thereby maintain it within mature sperm. WAGO-3 is a so-called argonaute protein that, bound with a small-RNA co-factor, is required to regulate gene expression. Its transmission into the embryo via sperm has functional relevance to the embryo, and its regulation by PEI-1 represents an important step in the transmission of extrachromosomal information, in the form of small RNAs, across generations. The described studies primarily aim to decipher how PEI-1 and WAGO-3 interact and how this interaction preserves WAGO-3 during spermatogenesis. In addition, the proposed experiments will shed light on how WAGO-3 is found in different phase-separated structures depending on developmental state and its loading with a small-RNA cofactor.

• DFG Programme: Research Grants