The TRIM-NHL Protein LIN-41 Controls the Onset of Developmental Plasticity in Caenorhabditis elegans

Abstract

The mechanisms controlling cell fate determination and reprogramming are fundamental for development. A profound reprogramming, allowing the production of pluripotent cells in early embryos, takes place during the oocyte-to-embryo transition. To understand how the oocyte reprogramming potential is controlled, we sought Caenorhabditis elegans mutants in which embryonic transcription is initiated precociously in germ cells. This screen identified LIN-41, a TRIM-NHL protein and a component of the somatic heterochronic pathway, as a temporal regulator of pluripotency in the germline. We found that LIN-41 is expressed in the cytoplasm of developing oocytes, which, in lin-41 mutants, acquire pluripotent characteristics of embryonic cells and form teratomas. To understand LIN-41 function in the germline, we conducted structure-function studies. In contrast to other TRIM-NHL proteins, we found that LIN-41 is unlikely to function as an E3 ubiquitin ligase. Similar to other TRIM-NHL proteins, the somatic function of LIN-41 is thought to involve mRNA regulation. Surprisingly, we found that mutations predicted to disrupt the association of LIN-41 with mRNA, which otherwise compromise LIN-41 function in the heterochronic pathway in the soma, have only minor effects in the germline. Similarly, LIN-41-mediated repression of a key somatic mRNA target is dispensable for the germline function. Thus, LIN-41 appears to function in the germline and the soma via different molecular mechanisms. These studies provide the first insight into the mechanism inhibiting the onset of embryonic differentiation in developing oocytes, which is required to ensure a successful transition between generations.

Author Summary

Reprogramming into a naïve, pluripotent state during the oocyte-to-embryo transition is directed by the oocyte cytoplasm. To understand how this reprogramming is controlled, we searched for C. elegans mutants in which the activation of embryonic genome, a landmark event demarcating the switch from a germline- to embryo-specific transcription, is initiated precociously in germ cells. This screen identified a novel function for LIN-41, a member of the TRIM-NHL protein family, in preventing a premature onset of embryonic-like differentiation and teratoma formation in developing oocytes, thus ensuring a successful passage between generations. This is the first example of such a regulator in cells that are poised for embryonic development. Interestingly, the majority of molecular “roadblocks” to reprograming that have been identified so far are epigenetic regulators. However, we propose that, at least in germ cells, LIN-41-like regulators may fulfill an analogous role in the cytoplasm, which has possible implications for the generation of human pluripotent stem cells.