Biology subjects

Shcherbata, H. R.

Publications and source records attributed to Shcherbata, H. R..

5 recordsLinked to original sources

bioRxiv2026

Argonaute 1 associates with nucleolar snoRNP machinery and regulates pre-rRNA levels and cell growth

Argonaute proteins are best known as cytoplasmic effectors of small-RNA-mediated gene silencing, although their compartment-specific functions remain incompletely understood. Here, we identify a previously unrecognized nucleolar role for Drosophila Argonaute 1 (AGO1). We observed stress-induced redistribution of AGO1 into cytoplasmic and nuclear ribonucleoprotein assemblies, whereas a distinct AGO1 pool consistently localized to Fibrillarin-positive nucleoli. Co-immunoprecipitation further showed that AGO1 associates with Fibrillarin-containing complexes in vivo. Re-analysis of AGO1-associated small-RNA sequencing data revealed snoRNAs, particularly C/D box snoRNAs, among AGO1-bound RNA species and increased snoRNA representation following AGO1 overexpression. Structural modelling demonstrated that simultaneous molecular interaction of AGO1 and the Fibrillarin-containing snoRNP machinery with the same snoRNA is stereochemically feasible, providing a structural framework for their potential association within a nucleolar snoRNP assembly. Functionally, AGO1 depletion reduced pre-rRNA levels and decreased both nucleolar and cell size in the follicular epithelium. Depletion of Dicer-1 did not reproduce these growth defects, arguing against a general consequence of impaired miRNA biogenesis. Together, these findings identify AGO1 as a nucleolar regulator that associates with snoRNP machinery and links small-RNA biology to pre-rRNA homeostasis and cell growth.

cell biology↗

bioRxiv2026

A conserved serotonin receptor pathway is a druggable modifier of Tau pathology, neural circuit formation and neurodegeneration

Tauopathies are devastating neurodegenerative disorders characterized by Tau hyperphosphorylation, neurofibrillary tangle (NFT) formation, neuronal dysfunction, and cognitive decline. Here, we establish a new Drosophila tauopathy model expressing eGFP-tagged human TauWT or the disease-associated TauP301L variant in the nervous system. TauP301L expression recapitulates key pathological and behavioral hallmarks of tauopathy, including elevated Tau hyperphosphorylation, accumulation of NFT-like, pTau-positive assemblies in vivo, reduced lifespan, hyperactivity, sleep loss, progressive locomotor decline, and age-dependent brain degeneration. Strikingly, TauP301L also disrupts the architecture of the mushroom body, a learning- and memory-related circuit in Drosophila, revealing an early disruption of neural circuit formation that is distinct from adult neurodegenerative phenotypes. We further show that suppression of serotonin 5-HT7R-CDK5 signaling pathway, either by genetic knockdown or pharmacological inhibition with inverse agonist, rescues Tau-induced behavioral and anatomical phenotypes. These findings identify 5-HT7R signaling as a conserved and druggable modifier of Tau toxicity and establish this model as a powerful in vivo platform for mechanistic studies and therapeutic discovery in tauopathies.

neuroscience↗

bioRxiv2024

Tumor suppressor miR-317 and lncRNA Peony are expressed from a polycistronic non-coding RNA locus that regulates germline differentiation and testis morphology

The impact of non-coding RNAs on stem cell biology and differentiation processes is an important and incompletely understood area of research. Using the testes of Drosophila melanogaster as a valuable system for investigating these processes, we identified a polycistronic locus from which two non-coding transcripts, miR-317 and the long non-coding RNA (lncRNA) Peony, are produced, with alternative polyadenylation implicated in regulation of their differential expression levels. We report here that each transcript has a distinct role in Drosophila testes; the increased expression of Peony results in the disruption of the muscle sheath covering the testis, and the absence of miR-317 leads to the emergence of germ-cell tumors in developing flies. The deficiency of miR-317 increases Notch signaling activity in somatic cyst cells, upregulates multiple predicted targets of miR-317, and drives germline tumorigenesis. Our findings establish miR-317 as a tumor suppressor controlling Notch signaling strength and uncover alternative polyadenylation as an unrecognized mechanism governing miRNA expression.

molecular biology↗

bioRxiv2022

Signaling through the Dystrophin Glycoprotein Complex affects the stress-dependent transcriptome in Drosophila

The Dystrophin Glycoprotein Complex (DGC) is a cell membrane-spanning complex that links the extracellular matrix with the intracellular cytoskeleton. Deficiencies in the DGC in humans cause muscular dystrophies (MDs), a group of inherited, incurable disorders associated with heterogeneous muscle, brain, and eye anomalies. To advance disease diagnostics and develop new treatment strategies, it is essential to understand the genetic pathways that are perturbed by DGC mutations and the mechanisms underlying these pathologies. Stresses such as nutrient deprivation and aging cause a reduction of muscle mass can be exacerbated by a reduced content of the DGC in membranes, whose integrity is vital for muscle health and function. This illustrates that the DGC plays a role in stress-response pathways. Therefore, it is important to investigate the influence of stress not only on healthy individuals but also on the wellbeing of MD patients. Moreover, the DGC has also emerged as an integral component in multiple signaling pathways, demonstrating an important yet poorly understood connection between intercellular forces and regulation of gene expression and illustrating the importance of understanding DGC-related transcriptional effects. Here, we utilize a Drosophila model to investigate the transcriptomic changes in mutants of four different DGC components under unstressed, temperature-stressed, and starvation-stressed conditions. Our analysis reveals a group of genes that exhibit DGC-dependent gene regulation. We identify large groups of genes that are differentially regulated in response to either temperature or starvation stress. Importantly, we also identify groups of genes with expression patterns dependent on the DGC signaling pathway for a proper stress response. This work reveals a novel function of the DGC in stress-response signaling. The view of the DGC as a regulatory unit involved in the stress response will give new insights into the etiology of symptoms of MDs and possible directions of symptomatic treatment and relief, and it will ultimately aid in a better understanding of DGC signaling and regulation under normal and stress conditions.

systems biology↗

bioRxiv2020

Tissue-specific regulation of translational readthrough tunes functions of the Traffic Jam transcription factor

Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR is pervasive in eukaryotic organisms; however, its biological significance remains unclear. In this study, we quantify the TR potential of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). We used CRISPR/Cas9 generated mutant flies to show that the TR-generated Tj isoform is expressed in the nuclei of a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads, which express the short Tj isoform only. Translational control of TR is critical for preservation of neuronal integrity and maintenance of reproductive health. Fine-tuning of the gene regulatory functions of transcription factors by TR provides a new potential mechanism for cell-specific regulation of gene expression. HighlightsO_LITj undergoes tissue-specific TR in neural cells of the central nervous system. C_LIO_LIStrict control of TR is crucial for neuroprotection and maintenance of reproductive capacity. C_LIO_LITR selectively fine-tunes the gene regulatory functions of the transcription factor. C_LIO_LITR in Tj links transcription and translation of tissue-specific control of gene expression. C_LI O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/411694v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1e6fb7dorg.highwire.dtl.DTLVardef@188d5c0org.highwire.dtl.DTLVardef@894173org.highwire.dtl.DTLVardef@127f4ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗