bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.04.13.040121

FOXO regulates neuromuscular junction homeostasis during Drosophila aging

Birnbaum, A.·Chang, K.·Bai, H.
View original source ↗Export metadata ↓

Abstract

The transcription factor FOXO is a known regulator of lifespan extension and tissue homeostasis. It has been linked to the maintenance of neuronal processes across many species, and has been shown to promote youthful characteristics by regulating cytoskeletal flexibility and synaptic plasticity at the neuromuscular junction (NMJ). However, the role of FOXO in aging neuromuscular junction function has yet to be determined. We profiled adult Drosophila FOXO-null mutant abdominal ventral longitudinal muscles and found that young mutants exhibited morphological profiles similar to those of aged wild-type flies, such as larger bouton areas and shorter terminal branches. We also observed changes to the axonal cytoskeleton and an accumulation of late endosomes in FOXO null mutants and motor neuron-specific FOXO knockdown flies, similar to those of aged wild-types. Motor neuron-specific overexpression of FOXO can delay age-dependent changes to NMJ morphology, suggesting FOXO is responsible for maintaining NMJ integrity during aging. Through genetic screening, we identify several downstream factors mediated through FOXO-regulated NMJ homeostasis, including genes involved in the p38-MAPK pathway. Interestingly, the phosphorylation of p38 and ERK were increased in the motor neuron-specific FOXO knockdown flies, suggesting FOXO acts as a suppressor of MAPK activation. Our work reveals that FOXO is a key regulator for NMJ homeostasis, and it maintains NMJ integrity by repressing MAPK signaling during aging.

Source connections

Explore related subjects

molecular biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Birnbaum, A., Chang, K., Bai, H.. 2020-04-14. FOXO regulates neuromuscular junction homeostasis during Drosophila aging. https://doi.org/10.1101/2020.04.13.040121

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Fatty Acid Synthase Binds Cellular mRNAs and its Depletion Reduces Translational Efficiency

Metabolic enzymes with non-canonical RNA binding activity have drawn a growing interest, due to their implications for basic biology and disease. Here we present the first endogenous RNA interactome of fatty acid synthase (FASN), an emerging oncological and virological target. Utilizing crosslinking-based approaches, we characterize the direct RNA association of FASN in two human cell lines, identifying over 6000 binding sites across over 3500 protein-coding genes, with a striking preference for the 5' UTR. We provide a functional cross-screen on the effects of FASN depletion on cellular translation. This integration with ribosome profiling indicated a preferential reduction in the translational efficiencies of FASN-associated mRNAs - an effect shown to be dependent on binding location and site number. Associated transcripts were enriched for morphogenic and cell division-related functions, as well as palmitoylated proteins. This correlative work primes further investigation of FASN as a regulator of translation of its target mRNAs.

molecular biology↗
bioRxiv2026

Genomic features and instability of linezolid resistance in vancomycin-resistant Enterococcus faecalis ST525

This study investigated the mechanisms of oxazolidinone resistance and genomic background in clinical ST525 Enterococcus faecalis isolates, a poorly characterized lineage reported in Brazilian hospitals as either vancomycin-resistant (VRE) or linezolid- and vancomycin-resistant (LVRE). Five LVREfs from intensive care unit patients (linezolid MICs, 8-32 mg/L; vancomycin MICs, >256 mg/L) carried only G2576T and G2505A (in three of four rrl copies) as known linezolid resistance determinants, despite variable linezolid MICs. During serial in vitro passages without antibiotic pressure, isolates with initial MICs of 8-16 mg/L exhibited progressive MIC reductions accompanied by reversion of mutant to wild-type rrl copies, whereas the isolate with an initial MIC of 32 mg/L maintained high-level resistance without reversion. Additional domain V substitutions emerged during MIC decline, while growth kinetics remained broadly similar. Whole-genome sequencing of a representative isolate (LVREfs L7) revealed a ~2.8-Mb chromosome enriched in mobile genetic elements (~8.6%), lacking a functional CRISPR-Cas system. A plasmid-borne prototype Tn1546 carrying vanA, devoid of internal insertion sequences, was found inserted into a Tn3-family transposase gene, a platform not typically associated with vanA mobilization. Together, these findings indicate that ST525 LVREfs, whose genomic features are consistent with long-term persistence in hospitals, may pose a challenge to routine susceptibility testing. A single mutational mechanism can yield variable linezolid MICs, and the ratio of mutated vs wild-type rrl copies can become heterogeneous in the absence of antibiotic pressure, without correlating directly with these values, contrary to the well-documented copy number-MIC correlation.

molecular biology↗
bioRxiv2026

Global repression of mesenchymal genes in epithelial cells by the histone demethylase LSD1

Epithelial-mesenchymal transition (EMT) is an essential process in development, tissue repair, and tumour metastasis, and is triggered by SNAI, ZEB and TWIST transcription factors, that recruit lysine-specific demethylase 1 (LSD1) to repress epithelial genes such as E-cadherin. In mesenchymal cells, LSD1 inhibition restores E-cadherin expression and reduces migration and invasion, consistent with LSD1 inhibition reverting EMT, and offering a therapeutic modality for EMT-associated disease. Recent data, however, suggest context-dependent roles for LSD1, as its inhibition in epithelial cells increases mesenchymal marker expression, potentially promoting EMT. To investigate this discrepancy, we mapped genome-wide binding of LSD1 in HCT116 epithelial cells and used rapid degron-mediated ablation of endogenous LSD1 to measure changes in nascent and steady-state transcription and chromatin accessibility. In epithelial cells, LSD1 binds constitutively-accessible, primed mesenchymal promoters. These are rapidly derepressed after LSD1 ablation, with activation of SNAI2 and ZEB1, which repress epithelial hallmarks such as E-cadherin. Re-introduction of LSD1 downregulates SNAI2 and ZEB1 but, surprisingly, further represses E-cadherin, indicating sustained loss of epithelial characteristics. Collectively, our results show that LSD1 maintains epithelial identity by repressing mesenchymal genes, questioning the therapeutic utility of LSD1 inhibition for EMT control.

molecular biology↗