TDP-1 and FUST-1: The Dynamic Duo in Exon Inclusion Inhibition and Fertility Control

2025-07-11 12:00

Keywords: TDP-1, FUST-1, CEH-14, pqn-41, transcriptional regulation, exon inclusion

Introduction 

Eukaryotic gene expression is a multistep process, and the interaction between different regulatory levels is crucial for coordinating gene expression. Transcription factors (TFs) and RNA-binding proteins (RBPs) are two major classes of proteins that regulate gene expression. Although the regulatory functions of individual TFs and RBPs have been well elucidated, research on how they work together across multiple regulatory levels to control gene expression is still lacking. Recently, a study published in Nucleic Acids Research has revealed interesting findings about TDP-1 and FUST-1, two genes related to amyotrophic lateral sclerosis (ALS)-associated RBPs, in terms of their co-inhibition of exon inclusion and their collaborative control of fertility with transcriptional regulation.

Construction of SunyBiotech 

SunyBiotech constructed pqn-41 and clec-190 mutants to reveal the role of gene regulation：

PHX6090：pqn-41 (syb6090)

PHX3345：clec-190 (syb3345)

1.Synergistic action of TDP-1 and FUST-1

Researchers carried out a systematic reverse genetic interaction screen in Caenorhabditis elegans (C. elegans), combining RBP and TF mutants to generate over 100 RBP; TF double mutants. It was found that the double mutants of TDP-1 and FUST-1 with CEH-14 both exhibited strong temperature-sensitive fertility defects (Fig. 1A-1B), including defects in gonad morphology and function (Fig. 1C), sperm dysfunction (Fig. 1D), and oocyte defects (Fig. 1E). However, when TDP-1, FUST-1 or CEH-14 was individually knocked out, the health of the worms was not affected (Fig. 1F-1G). This indicates that TDP-1 and FUST-1 jointly play a key role in regulating fertility in the context of CEH-14 mutation.

Figure 1. Synergistic action of TDP-1 and FUST-1

2. Transcriptional regulation and exon inclusion inhibition

Further research revealed that CEH-14 was a major transcriptional regulator (Fig. 2A), while TDP-1 and FUST-1 regulate splicing by jointly inhibiting exon inclusion (Fig. 2B and 2C). In TDP-1 mutants, an exon of the polyglutamine repeat protein PQN-41 was abnormally included (Fig. 2D), and in TDP-1; CEH-14 double mutants, fertility was restored by genetically forcing the skipping of this exon (Fig. 2E), indicating that PQN-41 gene splicing led to the temperature-dependent fertility defects.

Figure 2. Transcriptional regulation and exon inclusion inhibition

3. Evolutionary conservation

Researchers also explored the evolutionary conservation of tdp-1/TDP-43 and fust-1/FUS in inhibiting exon inclusion. They reanalyzed splicing microarray data from mouse brains with FUS or TDP-43 knockdown and found significant overlap between these two RBPs in regulating cassette exons (Fig. 3A). Similar to the results in C. elegans, exons regulated by both FUS and TDP-43 in mouse brains also tended to be jointly inhibited by the two (Fig. 3B). This shows that tdp-1/TDP-43 and fust-1/FUS tend to coordinately inhibit exon inclusion in both C. elegans and mouse brains.

Figure 3. Evolutionary conservation

Conclusion

This study not only reveals the common physiological role of TDP-1 and FUST-1 in promoting fertility in C. elegans but also clarifies their shared molecular function in inhibiting exon inclusion. These findings provide a new perspective for understanding the synergistic action of TDP-1 and FUST-1 in gene expression regulation and offer new clues for studying neurodegenerative diseases related to these genes, such as ALS and frontotemporal dementia (FTD). Future research can further explore the functional conservation of TDP-1 and FUST-1 in other biological models and their specific mechanisms of action in human diseases, in the hope of providing new targets and strategies for the treatment of related diseases.

References

Taylor M, Marx O, Norris A. TDP-1 and FUST-1 co-inhibit exon inclusion and control fertility together with transcriptional regulation. Nucleic Acids Res. 2023 Oct 13;51(18):9610-9628.