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cruzi and mass spectrometry data.Responsiveness to external cues is a hallmark of biological systems. In complex environments, it is crucial for organisms to remain responsive to specific inputs even as other internal or external factors fluctuate. Here, we show how the nematode Caenorhabditis elegans can discriminate between different food levels to modulate its lifespan despite temperature perturbations. This end-to-end robustness from environment to physiology is mediated by food-sensing neurons that communicate via transforming growth factor β (TGF-β) and serotonin signals to form a multicellular gene network. Specific regulations in this network change sign with temperature to maintain similar food responsiveness in the lifespan output. In contrast to robustness of stereotyped outputs, our findings uncover a more complex robustness process involving the higher order function of discrimination in food responsiveness. this website This process involves rewiring a multicellular network to compensate for temperature and provides a basis for understanding gene-environment interactions. Together, our findings unveil sensory computations that integrate environmental cues to govern physiology.Cerebellar neurons can signal sensory and motor events, but their role in active sensorimotor processing remains unclear. We record and manipulate Purkinje cell activity during a task that requires mice to rapidly discriminate between multisensory and unisensory stimuli before motor initiation. Neuropixels recordings show that both sensory stimuli and motor initiation are represented by short-latency simple spikes. Optogenetic manipulation of short-latency simple spikes abolishes or delays motor initiation in a rate-dependent manner, indicating a role in motor initiation and its timing. Two-photon calcium imaging reveals task-related coherence of complex spikes organized into conserved alternating parasagittal stripes. The coherence of sensory-evoked complex spikes increases with learning and correlates with enhanced temporal precision of motor initiation. These results suggest that both simple spikes and complex spikes govern sensory-driven motor initiation simple spikes modulate its latency, and complex spikes refine its temporal precision, providing specific cellular substrates for cerebellar sensorimotor control.CELF6 is a CELF-RNA-binding protein, and thus part of a protein family with roles in human disease; however, its mRNA targets in the brain are largely unknown. Using cross-linking immunoprecipitation and sequencing (CLIP-seq), we define its CNS targets, which are enriched for 3' UTRs in synaptic protein-coding genes. Using a massively parallel reporter assay framework, we test the consequence of CELF6 expression on target sequences, with and without mutating putative binding motifs. Where CELF6 exerts an effect on sequences, it is largely to decrease RNA abundance, which is reversed by mutating UGU-rich motifs. This is also the case for CELF3-5, with a protein-dependent effect on magnitude. Finally, we demonstrate that targets are derepressed in CELF6-mutant mice, and at least two key CNS proteins, FOS and FGF13, show altered protein expression levels and localization. Our works find, in addition to previously identified roles in splicing, that CELF6 is associated with repression of its CNS targets via the 3' UTR in vivo.Many bacteria contain an RNA repair operon, encoding the RtcB RNA ligase and the RtcA RNA cyclase, that is regulated by the RtcR transcriptional activator. Although RtcR contains a divergent version of the CARF (CRISPR-associated Rossman fold) oligonucleotide-binding regulatory domain, both the specific signal that regulates operon expression and the substrates of the encoded enzymes are unknown. We report that tRNA fragments activate operon expression. Using a genetic screen in Salmonella enterica serovar Typhimurium, we find that the operon is expressed in the presence of mutations that cause tRNA fragments to accumulate. RtcA, which converts RNA phosphate ends to 2', 3'-cyclic phosphate, is also required. Operon expression and tRNA fragment accumulation also occur upon DNA damage. The CARF domain binds 5' tRNA fragments ending in cyclic phosphate, and RtcR oligomerizes upon binding these ligands, a prerequisite for operon activation. Our studies reveal a signaling pathway involving broken tRNAs and implicate the operon in tRNA repair.Regulator of telomere length 1 (RTEL1) is an essential helicase that maintains telomere integrity and facilitates DNA replication. The source of replication stress in Rtel1-deficient cells remains unclear. Here, we report that loss of RTEL1 confers extensive transcriptional changes independent of its roles at telomeres. The majority of affected genes in Rtel1-/- cells possess G-quadruplex (G4)-DNA-forming sequences in their promoters and are similarly altered at a transcriptional level in wild-type cells treated with the G4-DNA stabilizer TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine). Failure to resolve G4-DNAs formed in the displaced strand of RNA-DNA hybrids in Rtel1-/- cells is suggested by increased R-loops and elevated transcription-replication collisions (TRCs). Moreover, removal of R-loops by RNaseH1 overexpression suppresses TRCs and alleviates the global replication defects observed in Rtel1-/- and Rtel1PIP_box knockin cells and in wild-type cells treated with TMPyP4. We propose that RTEL1 unwinds G4-DNA/R-loops to avert TRCs, which is important to prevent global deregulation in both transcription and DNA replication.Nuclear import receptors, also called importins, mediate nuclear import of proteins and chaperone aggregation-prone cargoes (e.g., neurodegeneration-linked RNA-binding proteins [RBPs]) in the cytoplasm. Importins were identified as modulators of cellular toxicity elicited by arginine-rich dipeptide repeat proteins (DPRs), an aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mechanistically, the link between importins and arginine-rich DPRs remains unclear. Here, we show that arginine-rich DPRs (poly-GR and poly-PR) bind directly to multiple importins and, in excess, promote their insolubility and condensation. In cells, poly-GR impairs Impα/β-mediated nuclear import, including import of TDP-43, an RBP that aggregates in C9orf72-ALS/FTD patients. Arginine-rich DPRs promote phase separation and insolubility of TDP-43 in vitro and in cells, and this pathological interaction is suppressed by elevating importin concentrations. Our findings suggest that importins can decrease toxicity of arginine-rich DPRs by suppressing their pathological interactions.
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