Tdrd6a Regulates the Aggregation of Buc into Functional Subcellular Compartments that Drive Germ Cell Specification

Abstract

SummaryPhase separation represents an important form of subcellular compartmentalization. However, relatively little is known about how the formation or disassembly of such compartments is regulated. In zebrafish, the Balbiani body (Bb) and the germ plasm (Gp) are intimately linked phase-separated structures essential for germ cell specification and home to many germ cell-specific mRNAs and proteins. Throughout development, these structures occur as a single large aggregate (Bb), which disperses throughout oogenesis and upon fertilization accumulates again into relatively large assemblies (Gp). Formation of the Bb requires Bucky ball (Buc), a protein with prion-like properties. We found that the multi-tudor domain-containing protein Tdrd6a interacts with Buc, affecting its mobility and aggregation properties. Importantly, lack of this regulatory interaction leads to significant defects in germ cell development. Our work presents insights into how prion-like protein aggregations can be regulated and highlights the biological relevance of such regulatory events.

Functional equivalence of germ plasm organizers

“…These molecules are probably not the only components of the complex and might contain additional proteins or RNAs, since numerous, canonical germ plasm components are conserved in metazoan genomes [reviewed in 35 , 82 , 83 ]. For instance, while this manuscript was under revision, the Tudor protein Tdrd 6 was shown to interact with Buc in zebrafish [ 84 ]. This interesting study suggests that the Tdrd6 interaction controls the aggregation of Buc.…”

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

“…The Bb is a large, electron-dense "aggregate" in oocytes, enriched in germline-specific mRNAs and a single protein with a prion-like LCD, called Xvelo in C. elegans or Bucky ball (Buc) in zebrafish (6,7). The C terminus of Buc contains a tri-RG motif that is symmetrically dimethylated and is required for Bb formation: Arg-methylated Buc recruits the Tudor-domain containing protein Tdrd6, which regulates Buc aggregation and promotes Bb assembly and hence is essential for germ cell development (61). Other examples where Arg-methylation promotes RNP assembly through recruitment of the Tudor-domain containing protein SMN include the symmetrically dimethylated snRNP proteins SmD1 and SmD3 and the asymmetrically dimethylated protein FUS.…”

A guide to regulation of the formation of biomolecular condensates

“…Similar to acetylation, protein methylation thus far has been found mostly to disfavor phase separation of proteins in vitro , as observed for FUS, hnRNPA2, and FMRP . It can also have an opposite effect; for example, symmetric dimethylation of Arg residues in Bucky ball (Buc) protein mediates tight interaction with the Tudor domains of Tdrd6a and mediates the formation of Balbiani bodies driving germ cell specification . Methylation of mRNA to form m6A has been also able to enhance phase separation .…”