Biology subjects

Gavin, R.

Publications and source records attributed to Gavin, R..

6 recordsLinked to original sources

bioRxiv2026

Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

ADGRD1 (GPR133) is an orphan adhesion G protein-coupled receptor (aGPCR) that primarily signals through Gs to regulate intracellular cAMP levels and is increasingly recognized for its roles across multiple tissues, including the central nervous system. Its conserved expression in neural tissues, the presence of splice variants in the fetal brain, and its structural similarity to other aGPCRs all suggest that it might play important roles in the organization of neural circuits. Recent studies have identified a wide range of extracellular, membrane- associated, and intracellular interacting partners, highlighting the receptors ability to integrate diverse signals. In this study, we explored the consequences of Adgrd1 deficiency in mice using behavioral, electrophysiological, and transcriptomic approaches. Adgrd1-null mice showed reduced nest-building behavior and decreased exploratory drive, while motor coordination and recognition memory remained largely intact. Electrophysiological recordings indicated a trend toward impaired long-term potentiation. These mice also exhibit increased susceptibility to kainate-induced excitotoxicity. RNA-seq analysis revealed coordinated changes in genes associated with inhibitory signaling, extracellular matrix organization, and cytoskeletal regulation, pointing to a shift toward reduced synaptic stabilization and increased hippocampal vulnerability. Altogether, these results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.

neuroscience↗

bioRxiv2025

Optogenetic activation of entorhinal projection neurons alters the target recognition and circuit development without enhancing axon regeneration after axotomy in organotypic slices.

The central nervous system (CNS) has a limited intrinsic capacity for axonal regeneration, making functional recovery after injury extremely challenging. Numerous strategies have been explored to overcome this blockade, among others, molecular interventions or modulation of the inhibitory extracellular environment. Despite some advances, effective regeneration remains elusive, particularly in adult CNS neurons. To investigate these mechanisms in a controlled and reproducible setting, we employ organotypic slice cultures (OSCs), which retain key structural and cellular features of the intact brain while allowing for long-term in vitro experimentation. In particular, the entorhino-hippocampal (EH) co-culture model preserves the anatomical and functional connectivity of the perforant pathway, providing an excellent platform for studying axonal degeneration and regeneration. This model reproduces laminar specificity, axonal myelination, and inhibitory signaling after axotomy, closely mimicking in vivo conditions. Furthermore, EH co-cultures facilitate the application of optogenetic tools to monitor and manipulate neuronal activity. Our study explores whether enhancing activity in entorhinal cortex neurons can promote axonal regeneration after a EH lesion. Our results show that increased activity in entorhinal neurons alters the development of the EH connection and fails to enhance the regrowth of injured mature entorhinal axons. These findings suggest that both extrinsic and intrinsic factors shape the regenerative response and highlight the utility of EH OSCs as a versatile model for testing future pro-regenerative interventions.

neuroscience↗

bioRxiv2024

Whole-Genome Sequencing of the Wild Barley Diversity Collection: A Resource for Identifying and Exploiting Genetic Variation for Cultivated Barley Improvement

To exploit allelic variation in Hordeum vulgare subsp. spontaneum, the Wild Barley Diversity Collection was evaluated for several agronomic traits and subjected to paired-end Illumina sequencing at [~]9X depth, generating 109.5 million single nucleotide polymorphisms after alignment to the Morex V3 assembly. A genome-wide association study of lemma color identified one marker-trait association (MTA) on chromosome 1HL close to HvBlp, the cloned gene controlling black lemma. Four MTAs were identified for stem rust resistance: one co-locating to the complex RMRL1-RMRL2 locus on 5HL, and three novel loci on 1HS, 1HL, and 5HL. Six MTAs for days to heading (DTH) on vernalized plants were identified on all chromosomes except 1H and 6H. Two MTAs for DTH on non-vernalized plants were identified on chromosomes 1HL and 2HS. All MTAs for DTH were novel. The whole genome sequence data described herein will facilitate the identification and utilization of new alleles for barley improvement.

genomics↗

bioRxiv2024

HuR-dependent expression of RyR2 contributes to calcium-mediated thermogenesis in brown adipocytes

Several uncoupling protein 1 (UCP1)-independent thermogenic pathways have been described in thermogenic adipose tissue, including calcium-mediated thermogenesis in beige adipocytes via sarco/endoplasmic reticulum ATPase (SERCA). We have previously shown that adipocyte-specific deletion of the RNA binding protein human antigen R (HuR) results in thermogenic dysfunction independent of UCP1 expression. RNA sequencing revealed the downregulation of several genes involved in calcium ion transport upon HuR deletion. The goal of this work was to define the HuR-dependent mechanisms of calcium driven thermogenesis in brown adipocytes. We generated (BAT)-specific HuR-deletion (BAT-HuR-/-) mice and show that their body weight, glucose tolerance, brown and white adipose tissue weights, and total lipid droplet size were not significantly different compared to wild-type. Similar to our initial findings in Adipo-HuR-/- mice, mice with BAT-specific HuR deletion are cold intolerant following acute thermal challenge at 4{degrees}C, demonstrating specificity of acute HuR-dependent thermogenesis to BAT. We also found decreased expression of ryanodine receptor 2 (RyR2), but no changes in RyR2, SERCA1, SERCA2, or UCP1 expression, in BAT from BAT-HuR-/- mice. Next, we used Fluo-4 calcium indicator dye to show that genetic deletion or pharmacological inhibition of HuR blunts the increase in cytosolic calcium concentration in SVF-derived primary brown adipocytes. Moreover, we saw a similar blunting in {beta}-adrenergic-mediated heat generation, as assessed by ERtherm AC fluorescence, in SVF-derived brown adipocytes following HuR inhibition or deletion. Mechanistically, we show that HuR directly binds and reduces the decay rate of RyR2 mRNA in brown adipocytes, and stabilization of RyR2 via S107 rescues {beta}-adrenergic-mediated cytosolic calcium increase and heat generation in HuR deficient brown adipocytes. In conclusion, our results suggest that HuR-dependent control of RyR2 expression plays a significant role in the thermogenic function of brown adipose tissue through modulation of SR calcium cycling.

molecular biology↗

bioRxiv2024

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer's disease in Prnp mutant mice and in the P301S transgenic tauopathy mice model

The natural cellular prion protein is known to play several roles during development and adult brain. Far from its pathological roles in prionopathies, the non-pathogenic cellular prion protein has been described as a receptor for several amyloid in oligomeric and prefibrillar forms. For some amyloids, specific domains of the protein play a crucial role in modulating amyloids cellular uptake and seeding properties. In most studies, the functions and the role of putative amyloid receptors have been analyzed by using brain extracts derived from human neurodegenerative patients. Another strategy has been to modify the genetic dosage of the natural prion protein in genetic models of different diseases. In this study, we take advantage of both approaches to examine whether this protein plays a role in the seeding and spreading of pathogenic tau. Our results point to a role of the natural prion protein in the emergence of pathogenic tau in a mouse model overexpressing the mutation P301S of the human tau gene. In contrast, its role is minor when sarkosyl-derived brain samples of Alzheimers disease are used. In fact, our results indicate that the use of this type of sample is not adequate to determine the role of a putative receptor in tau seeding and spreading.

neuroscience↗

bioRxiv2023

miR-519a-3p, found to regulate cellular prion protein during Alzheimer's disease pathogenesis, as a biomarker of asymptomatic stages

MiRNAs induce post-transcriptional gene silencing by binding to the 3-UTR of complementary messenger RNAs and causing either degradation or inhibition of translation. The clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. In this sense, diagnosis at asymptomatic stages of Alzheimers disease (AD) remains a challenge since it can only be made at autopsy according to Braak NFT staging. Achieving the objective of detecting AD at early stages would allow possible therapies to be addressed before the onset of cognitive impairment. Many studies have determined that the expression pattern of some miRNAs is deregulated in AD patients, but to date, none has been correlated with downregulated expression of cellular prion protein (PrPC) during disease progression. That is why, by means of cross studies of miRNAs up-regulated in AD with in silico identification of potential miRNAs-binding to 3UTR of human PRNP gene, we selected miR-519a-3p for our study. Other family members of miR-519 have been shown to bind to the 3UTR region of PRNP in vitro and presumably degrade PRNP mRNA. In addition, up-regulation of some of them has been reported in various tissues from AD patients, including cerebrospinal fluid, plasma, and blood serum. In fact, miR-519d-3p is marked as a bridge regulator between mild cognitive impairment and severe AD. However, none of the studies address the prodromal stages of the disease or the expression profile of miR-519 in other neurodegenerative diseases that also may present dementia. Therefore, in this study we analyzed miR-519a-3p expression in cerebral samples of AD at different stages of evolution as well as other neurodegenerative diseases such as other tauopathies and synucleinopathies. Our results show the specific and early upregulation of miR-519a-3p starting from Braak stage I of AD, suggesting its potential use as a biomarker of preclinical stages of the disease.

neuroscience↗