Biology subjects

Morelli, G.

Publications and source records attributed to Morelli, G..

9 recordsLinked to original sources

bioRxiv2026

Endogenous oxytocin reconfigures brainwide network dynamics toward salience-related states

Oxytocin (OXT) can exert diverse effects across social, affective and motivational domains, yet its impact on brain function at the systems level remains unclear. Here, we combine chemogenetics with fMRI and electrophysiology in mice to investigate how endogenous OXT reshapes intrinsic large-scale brain network dynamics. Using mice constitutively expressing hM3Dq DREADD receptors in OXT-releasing hypothalamic neurons, we show that chemogenetic stimulation of OXT neurons elicits widespread increases in cerebral blood volume, with prominent effects in fronto-striatal regions and dorsal hippocampal areas. This broad functional response is accompanied by a network-specific reconfiguration of brain-wide functional connectivity, characterized by increased coupling between key components of the rodent social brain, and negative functional coupling between hippocampal and fronto-cortical regions. In vivo electrophysiology under matched conditions shows concordant changes in slow (<1 Hz) and delta-band coherence across frontalthalamic and fronto-hippocampal circuits, revealing a plausible neural correlate of the observed connectivity effects. Notably, these changes are accompanied by a marked reconfiguration of the temporal architecture of fMRI network activity, with increased occupancy of co-activation states engaging saliencerelated regions and a concomitant suppression of sensory-dominated states. Together, these findings identify dynamic network-state reconfiguration as a systems-level mechanism through which endogenous OXT can tune functional communication across social-affective circuits.

neuroscience↗

bioRxiv2025

Endogenous retrotransposon reverse transcriptase supports osteocyte function: implications for antiretroviral therapy-associated bone loss

Retrotansposable elements such as LINE-1 and HERV-K encode endogenous reverse transcriptases (RTs) with emerging roles in human biology. People living with HIV, particularly those receiving nucleoside reverse transcriptase inhibitor (NRTI)-based therapy, have increased risk of low bone mineral density (BMD), but the underlying mechanisms remain unclear. Here we show that endogenous RT activity, estimated by L1-Ta and HERV-K DNA content, is enriched in human bone and markedly reduced in osteoporosis, where it correlates with BMD and osteocyte gene expression. In vitro, nucleoside reverse transcriptase inhibitors (NRTIs), widely used as antiretroviral drugs, impair osteocyte endocrine function, disrupting vitamin D3-induced FGF23 production and parathyroid hormone- mediated regulation of SOST. These findings identify endogenous RT activity as a regulator of osteocyte function and bone homeostasis, and suggest that its pharmacological inhibition may contribute to antiretroviral therapy-associated bone loss.

molecular biology↗

bioRxiv2025

Histone Succinylation-Driven LINE-1 Reactivation Links High-Fat Diet Stress to Hepatic Inflammation and Liver Disease

Endogenous retroelements such as LINE-1 (L1) are stress-responsive genomic elements increasingly implicated in stress induced inflammation and associated pathogenic states. Here, we uncover a novel mechanism whereby high-fat diet-associated palmitic acid stress triggers chromatin remodeling that derepresses L1 elements and an IRF3-dependent interferon response, leading to innate immune activation in hepatocytes. Mechanistically, we show that that palmitic acid exposure promoted p300/CBP-mediated H3K122 succinylation at L1 promoters, coupled with reduced sirtuin desuccinylase cofactor availability, thereby enhancing chromatin accessibility and transcription. Antisense oligonucleotide-mediated L1 silencing abrogated this response by resetting chromatin homeostasis, demonstrating a causal role for L1 in palmitate-induced inflammation. In vivo, L1 knockdown in a fructose-palmitate-cholesterol (FPC) diet-induced mouse model of MASLD/MASH improved insulin sensitivity, reduced hepatic inflammation, and ameliorated fibrosis. These findings identify L1 derepression as a key epigenetic and inflammatory effector of dietary lipid stress and establish L1 inhibition as a potential therapeutic strategy for metabolic liver disease.

molecular biology↗

bioRxiv2024

A shade-responsive microProtein in the Arabidopsis ATHB2 gene regulates elongation growth and root development

Shade triggers widespread changes in transcript isoform production in Arabidopsis thaliana. Using 5' PEAT sequencing, we identified 377 candidate microprotein-encoding transcripts arising from alternative transcription start sites, including one located within the third exon of ATHB2, a class II HD-ZIP transcription factor central to shade avoidance. The encoded microprotein, ATHB2miP, lacks the DNA-binding homeodomain but retains the leucine zipper domain, through which it forms heterodimers with full-length ATHB2, inhibits its DNA-binding activity, and disrupts its localization to nuclear photobodies. Ectopic expression of ATHB2miP phenocopies loss of ATHB2, deregulating genes involved in auxin signaling, root development, and iron homeostasis. Complementation of the athb2 mutant with a construct carrying a silent mutation at the ATHB2miP start codon results in exaggerated hypocotyl elongation under both white light and shade, demonstrating that ATHB2miP is required to restrain excessive elongation growth. Immunoprecipitation mass spectrometry confirmed that this mutation redirects translation to alternative initiation sites, producing distinct proteoforms absent from wild-type plants. Additionally, ATHB2 suppresses iron uptake genes, and iron availability modulates shade growth responses in an ATHB2-dependent manner. Together, these findings establish ATHB2miP as a regulator of an ATHB2 feedback circuit that integrates light and nutritional signals to coordinate shoot elongation and root development.

plant biology↗

bioRxiv2023

HD-Zip II transcription factors control distal stem cell fate in Arabidopsis roots by linking auxin signaling to the FEZ/SOMBRERO pathway

In multicellular organisms, specialized tissues are generated by specific populations of stem cells through cycles of asymmetric cell divisions, where one daughter undergoes differentiation and the other maintains proliferative properties. In Arabidopsis thaliana roots, the columella - a gravity-sensing tissue which protects and defines the position of the stem cell niche - represents a typical example of a tissue whose organization is exclusively determined by the balance between proliferation and differentiation. The columella derives from a single layer of stem cells through a binary cell fate switch that is precisely controlled by multiple, independent regulatory inputs. Here, we show that the HD-Zip II transcription factors HAT3, ATHB4, and AHTB2, redundantly regulate columella stem cell fate and patterning in the Arabidopsis root. The HD-Zip II transcription factors promote columella stem cell proliferation by acting as effectors of the FEZ/SMB circuit and, at the same time, by interfering with auxin signaling to counteract hormone-induced differentiation. Overall, our work shows that HD-Zip II connect two opposing parallel inputs to fine tune the balance between proliferation and differentiation in columella stem cells. Summary statementHD-Zip II transcription factors redundantly regulate columella stem cells activity by counteracting auxin-mediated differentiation downstream of the FEZ/SMB proliferative input

plant biology↗

bioRxiv2022

Lack of the glycine alpha 2 receptor impairs reward-motivated behavior and striatal signal integration.

Distinct developmental pathologies, including autism spectrum disorder and schizophrenia, exhibit impaired reward-motivated behavior. Key to proper reward-motivated behavior is dopamine-mediated modulation of striatal activity. The glycine alpha 2 receptor (GlyR2) is the single functionally expressed glycine receptor in adult striatum, and is therefore ideally positioned to modulate striatal behavior and cellular activity. Here, we report excessive appetitive conditioning in male GlyR2 knockout mice. We next show that depletion of GlyR2 enhances dopamine-induced increases in the activity of putative dopamine D1-expressing striatal projection neurons, while not affecting dopamine neuron activity. Moreover, we found that excessive locomotor responses to amphetamine in GlyR2 KO mice correlate with immediate early gene c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the number of activated cell ensembles in the striatum in response to D-amphetamine in GlyR2 KO mice. Taken together, we show that depletion of GlyR2 impairs reward-motivated behavior and altered striatal signal integration. This sheds important light onto the cellular mechanisms that underlie reward function, and pave the way towards novel therapeutics for the treatment of e.g. schizophrenia and addiction. Significance statementThe glycine receptor alpha 2 has long been studied for its role in development, with expression assumed to decline throughout adulthood in favor of the glycine receptor alpha 1 and 3. Yet, we showed that in the dorsal striatum, the glycine alpha 2 receptor is the only functionally expressed glycine receptor at adult age (Molchanova et al., 2017). In the present work, we show for the first time that the glycine alpha 2 receptor crucially affects striatal cell activity, which lies at the basis of reward-motivated behaviors, and which is impaired in many psychiatric pathologies. Indeed, a link between the mutations in the glycine alpha 2 receptor and autism as well as schizophrenia has been described, but a functional role for the glycine alpha 2 receptor in adult brain structures that are involved in psychiatric pathologies, was never shown before.

neuroscience↗

bioRxiv2020

ATP-Citrate lyase fuels axonal transport across species

Microtubule (MT)-based transport is an evolutionary conserved processed finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, which is catalyzed by the α-tubulin N-acetyltransferase 1, Atat1, promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanisms that controls Atat1 activity remains poorly understood. Here, we show that a pool of vesicular ATP-citrate lyase Acly acts as a rate limiting enzyme to modulate Atat1 activity by controlling availability of Acetyl-Coenzyme-A (Acetyl-CoA). In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in the pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine new light on the pathophysiological mechanisms underlying FD.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗

bioRxiv2020

DRT111/SFPS splicing factor controls ABA sensitivity in Arabidopsis seed development and germination

RNA splicing is a fundamental mechanism contributing to the definition of the cellular protein population in any given environmental condition. DRT111/SFPS is a splicing factor previously shown to interact with phytochromeB and characterized for its role in splicing of pre-mRNAs involved in photomorphogenesis. Here, we show that DRT111 interacts with Arabidopsis Splicing Factor 1 (SF1), involved in 3 splicing site recognition. Double and triple mutant analysis shows that DRT111 controls splicing of ABI3 and acts upstream of the splicing factor SUPPRESSOR OF ABI3-5 (SUA). DRT111 is highly expressed in seeds and stomata of Arabidopsis and is induced by long-term treatments with polyethylene glycol and ABA. DRT111 knock-out mutants are defective in ABA-induced stomatal closure and are hypersensitive to ABA during seed germination. Conversely, DRT111 over-expressing plants show ABA hyposensitive seed germination. RNAseq experiments show that in dry seeds, DRT111 controls expression and splicing of genes involved in response to osmotic stress and ABA, light signaling and mRNA splicing, including targets of ABSCISIC ACID INSENSITIVE3 (ABI3) and PHYTOCHROME INTERACTING FACTORs (PIFs). Consistently, expression of the germination inhibitor SOMNUS, induced by ABI3 and PIF1 is up-regulated in imbibed seeds of drt111-2 mutants. Altogether, these results indicate that DRT111 controls sensitivity to abscisic acid (ABA) during seed development, germination and stomatal movements and constitutes a point of integration of the ABA- and light-regulated pathways to control seed germination. One Sentence SummaryArabidopsis splicing factor DRT111/SFPS is required for ABA-mediated responses in seeds

plant biology↗

bioRxiv2019

ATAT1-enriched vesicles promote microtubule acetylation via axonal transport

Microtubules are polymerized dimers of - and {beta}-tubulin that underlie a broad range of cellular activities. Acetylation of -tubulin by the acetyl-transferase ATAT1 modulates microtubule dynamics and functions in neurons. However, it remains unclear how and why this enzyme acetylates microtubules over long distances in axons. Here, we show that loss of ATAT1 impairs axonal transport in neurons and cell free motility assays confirm a requirement of tubulin acetylation for proper bidirectional vesicular transport. Moreover, we demonstrate that the main cellular pool of ATAT1 is transported at the cytosolic side of neuronal vesicles that are moving along axons. Altogether, our data suggest that axonal transport of ATAT1-enriched vesicles is the predominant driver of -tubulin acetylation in axons.

neuroscience↗