Biology subjects

Zinter, M.

Publications and source records attributed to Zinter, M..

5 recordsLinked to original sources

bioRxiv2026

Arc Capsids Facilitate the Transfer of Muscleblind.

The Drosophila activity-regulated cytoskeletal-associated protein (dArc1) can facilitate viral-like synaptic transfer of its own mRNA through dArc1 capsid formation. This transfer promotes synaptic maturation at the Drosophila neuromuscular junction and shows conservation to the mammalian neural synapse through the dArc1 mammalian ortholog, Arc. Recently, we established that dArc1 can interact with several transcripts other than its own in Drosophila including the transcript of muscleblind (Mbl), an RNA splicing factor known to be involved in neuronal and muscle development. Here, we demonstrate this interaction is further conserved to Arc and the mammalian Mbl ortholog Muscleblind Like Splicing Regulator 1 (Mbnl1). In the mouse neuro2a (N2A) cell line, immunoprecipitation of Arc protein enriches for both the Arc and Mbnl1 transcript. Upon differentiation of N2A cells, the ability of Arc to bind its own transcript and Mbnl1 are abolished while potassium stimulation of these cells restored Arc interactions with both transcripts, indicating that this interaction is enhanced by neuronal activity. This interaction is further conserved to the mammalian central nervous system, where Mbnl1 shows increased colocalization with Arc protein in the dentate gyrus of foot-shocked mice. Furthermore, we demonstrate that both Arc and Mbnl1 RNA can be detected in extracellular vesicles (EVs), and that Mbnl1, unlike the Arc transcript, is not directly encapsulated by Arc protein. We additionally observe MblA crosses the Drosophila NMJ, likely within EVs, and postsynaptic MblA accumulation is dependent on presynaptic pools of dArc1. Taken together, our data suggest that Arc protein interacts with Mbnl1 RNA in an activity-dependent manner and this interaction may facilitate transsynaptic transfer of Mbnl1 RNA through EVs with implications for neurodevelopment. SignificanceThe immediate early gene Arc is known to play roles in LTP, LTD, memory and is dysregulated in diseases of the CNS in addition to forming a viral-like capsid to allow for intercellular transfer of its own mRNA in a pathway referred to as the Viral-Like Synaptic Transfer of RNA (ViSyToR). Investigating additional members of the ViSyToR pathway will help increase our understanding of how Arc can play such diverse roles in the CNS. In this study, we establish that transcript for Muscleblind is an additional ViSyToR member in both Drosophila and the mammalian CNS.

neuroscience↗

bioRxiv2025

Somatic function of the Argonaute protein Aubergine is essential for neuromuscular development and function in Drosophila

BackgroundThe PIWI-interacting RNA (piRNA) pathway is the primary defense against the deleterious activity of transposable elements (TEs), a role classically assigned to the germline. We recently discovered that the retrotransposon Copia is a negative regulator of synaptogenesis at the Drosophila larval neuromuscular junction (LNMJ) [1]. Here, we investigated whether the piRNA pathway regulates Copia in this somatic context. MethodsAnalysis of existing sequencing data revealed the expression of piRNA pathway components in somatic tissues [2]. We focused on Aubergine (aub), a core PIWI-clade Argonaute. We utilized CRISPR generated aub reporter lines and confocal microscopy to confirm the enrichment of AUB at the LNMJ and next generation sequencing coupled with digital PCR to validate the upregulation of TEs in aub knockdown larvae and adult tissues. ResultsData from genetic reporters and antibody staining show that AUB is expressed and localized to the LNMJ. Tissue-specific knockdown of aub at the LNMJ resulted in increased TE expression, including Copia. In contrast to the synaptic overgrowth seen with Copia depletion [1], aub reduction caused a decrease in synapse number and impaired motor function and lifespan. These phenotypes are consistent with the upregulation of Copia, a negative regulator of synapse growth. ConclusionsOur findings demonstrate that AUB functions somatically at the LNMJ to repress TEs, thereby ensuring proper neuromuscular development and function. This work establishes a physiological role for the piRNA pathway in a somatic tissue, linking TE repression to neuromuscular development.

neuroscience↗

bioRxiv2025

Rlim coordinates diurnal regulation of food intake and thermogenesis

Energy homeostasis in mice is maintained through coordinated activity among hypothalamic nuclei that regulate food intake and thermogenesis. These processes must adapt to the sleep-wake cycle, yet the underlying pathways, cell types, and molecular mechanisms governing their diurnal regulation remain poorly understood. We show that mice lacking the E3 ubiquitin ligase Rlim are lean and resistant to diet-induced obesity, owing to reduced food intake and enhanced brown adipose tissue (BAT) thermogenesis. We identify GABAergic neurons in the suprachiasmatic nucleus (SCN)--components of the central circadian clock--as mediators of these effects. Specifically, Rlim in RIP-Cre+ neurons governs daily thermogenic rhythms, while Rlim in vasoactive intestinal peptide (VIP)-expressing neurons modulates diurnal feeding behavior. Thus, Rlim is a key regulator of diurnal rhythms controlling energy balance.

physiology↗

bioRxiv2024

An orbitocortical-thalamic circuit suppresses binge alcohol-drinking.

Alcohol consumption remains a significant global health challenge, causing millions of direct and indirect deaths annually. Intriguingly, recent work has highlighted the prefrontal cortex, a major brain area that regulates inhibitory control of behaviors, whose activity becomes dysregulated upon alcohol abuse. However, whether an endogenous mechanism exists within this brain area that limits alcohol consumption is unknown. Here we identify a discrete GABAergic neuronal ensemble in the medial orbitofrontal cortex (mOFC) that is selectively recruited during binge alcohol-drinking and intoxication. Upon alcohol intoxication, this neuronal ensemble suppresses binge drinking behavior. Optogenetically silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. We find that this neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. We further show, using brain-wide analysis, that this neuronal ensemble projects widely, and that its projections specifically to the mediodorsal thalamus are responsible for regulating binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by halting alcohol intake. These results provide valuable insights into the complex nature of alcohol abuse and offers potential avenues for the development of mOFC neuronal ensemble-targeted interventions.

neuroscience↗

bioRxiv2018

Integrating Host Response and Unbiased Microbe Detection for Lower Respiratory Tract Infection Diagnosis in Critically Ill Adults

Lower respiratory tract infections (LRTI) lead to more deaths each year than any other infectious disease category(1). Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests(2). In critically ill patients, non-infectious inflammatory syndromes resembling LRTI further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the lung microbiome and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed rules-based and logistic regression models (RBM, LRM) in a derivation cohort of 20 patients with LRTI or non-infectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with non-infectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an AUC of 0.96 (95% CI = 0.86 - 1.00), the diversity metric with an AUC of 0.80 (95% CI = 0.63 - 0.98), and the host transcriptional classifier with an AUC of 0.91 (95% CI = 0.80 - 1.00). Combining all three achieved an AUC of 0.99 (95% CI = 0.97 - 1.00) and negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome and host transcriptome may hold promise as a novel tool for LRTI diagnosis.\n\nSIGNIFICANCE STATEMENTLower respiratory tract infections (LRTI) are the leading cause of infectious disease-related death worldwide yet remain challenging to diagnose because of limitations in existing microbiologic tests. In critically ill patients, non-infectious respiratory syndromes that resemble LRTI further complicate diagnosis and confound targeted treatment. To address this, we developed a novel metagenomic sequencing-based approach that simultaneously interrogates three core elements of acute airway infections: the pathogen, lung microbiome and host response. We studied this approach in a prospective cohort of critically ill patients with acute respiratory failure and found that combining pathogen, microbiome and host gene expression metrics achieved accurate LRTI diagnosis and identified etiologic pathogens in patients with clinically identified infections but otherwise negative testing.\n\nFundingNHLBI K12HL119997 (Langelier C), NHLBI K23HL123778 (Christensen S), NIAID P01AI091575 and the Chan Zuckerberg Biohub (DeRisi JL), NHLBI K23 HL136844 (Moazed F), NHLBI R01HL110969, K24HL133390, R35HL140026 (Calfee C), Gladstone Institutes (Pollard KS).

genomics↗