Gene expression is a multistep, carefully controlled process with distinct regulatory layers. Previous work in our lab suggested that crosstalk between these layers plays a significant role in coordinating gene expression. Recently, we embarked on a systematic reverse-genetic interaction screen with the goal of identifying functionally relevant coordination of gene expression across regulatory layers in the nervous system. We are particularly interested in crosstalk between transcription and RNA processing. We crossed previously-generated CRISPR-Cas9 RNA binding protein (RBP) deletions with existing transcription factor (TF) mutant strains, creating over a hundred RBP;TF double mutants. We screened these double mutants for unexpected phenotypes not seen in either of the constituent single mutants. A novel phenotype in the double mutant indicates a genetic interaction between the corresponding RBP and TF. The strongest double mutant phenotypes were further investigated to characterize underlying mechanisms that contribute to the phenotype. We have identified several strong genetic interactions by studying double mutants with a variety of unexpected phenotypes. Here, we present evidence that two ALS-related RBPs, FUST-1 and TDP-1, have a similar interaction with the transcription factor CEH-14. The loss of any one of these three genes alone has no significant effect on the overall health of the organism. However,
fust-1;
ceh-14 and
tdp-1;
ceh-14 double mutants both exhibit strong temperature-sensitive reproductive defects. Both double mutants, when grown at 25° C, exhibit deformed gonads, resulting in reduced egg production and correlating with an increased prevalence of males. RNA-seq results suggest that
fust-1;
ceh-14 and
tdp-1;
ceh-14 undergo similar gene dysregulation that cannot simply be explained by their shared
ceh-14 mutation. The similarity of the double mutant phenotypes suggests that these three genes are involved in the same process. Additionally, the lack of a similar phenotype in a
fust-1 tdp-1 double mutant implies that FUST-1 and TDP-1 interact with CEH-14, but not with each other. Our findings implicate an important role for CEH-14, FUST-1, and TDP-1 in orchestrating gonad development in C. elegans. The physiological roles of FUST-1 and TDP-1, as well as their human homologs FUS and TDP43, have not yet been fully characterized. We hope that our findings will shed light on a fundamental role that these RNA binding proteins share.