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SUMMARYNuclear pre-mRNA 3Ј-end processing is vital for the production of mature mRNA and the generation of the 3Ј untranslated region (UTR). However, the roles and regulation of this event in cellular development remain poorly understood. Here, we report the function of a nuclear pre-mRNA 3Ј-end processing pathway in synapse and axon formation in C. elegans. In a genetic enhancer screen for synaptogenesis mutants, we identified a novel polyproline-rich protein, Synaptic defective enhancer-1 (SYDN-1). Loss of function of sydn-1 causes abnormal synapse and axon development, and displays striking synergistic interactions with several genes that regulate specific aspects of synapses. SYDN-1 is required in neurons and localizes to distinct regions of the nucleus. Through a genetic suppressor screen, we found that the neuronal defects of sydn-1 mutants are suppressed by loss of function in Polyadenylation factor subunit-2 (PFS-2), a conserved WD40-repeat protein that interacts with multiple subcomplexes of the pre-mRNA 3Ј-end processing machinery. PFS-2 partially colocalizes with SYDN-1, and SYDN-1 influences the nuclear abundance of PFS-2. Inactivation of several members of the nuclear 3Ј-end processing complex suppresses sydn-1 mutants. Furthermore, lack of sydn-1 can increase the activity of 3Ј-end processing. Our studies provide in vivo evidence for pre-mRNA 3Ј-end processing in synapse and axon development and identify SYDN-1 as a negative regulator of this cellular event in neurons.

Understanding sex and gender differences is fundamental to rigorous and inclusive research, whether studying disease pathophysiology, sociodemographic determinants of health, or the benefits and harms of medical or social interventions. The inclusion of gender-diverse study populations has improved, but the reporting of sex and gender variables in research is still incomplete. The Sex and Gender Equity in Research (SAGER) guidelines, published in 2016, have been widely endorsed, but few scientific journals and organizations have incorporated them into formal editorial guidance and publication policies. To facilitate monitoring of and adherence to the SAGER guidelines in Lancet journals, we carried out an informal pilot study and developed a checklist to enable rapid editorial checks, promote uptake of the guidelines by other editors and journals, and raise awareness among peer reviewers and authors. By using this checklist as part of manuscript assessment and peer-review processes, journal editors can support best reporting practices when considering sex and gender as variables, improving the generalizability of the research they publish.