Biology subjects

Jiao, K.

Publications and source records attributed to Jiao, K..

11 recordsLinked to original sources

bioRxiv2026

Chronic Mild Stress Impairs Hippocampal Myelination through SOX6-Dependent Dysfunction of Oligodendrocyte Lineage Cells

Chronic stress induces structural and functional changes in the brain, increasing susceptibility to major depressive disorder and other mental illnesses. Myelination deficits are a key pathological feature of stress-related disorders, yet the molecular mechanisms linking chronic stress to oligodendrocyte dysfunction remain poorly understood. Here, we used single-nucleus multiome sequencing to map gene expression and chromatin-accessibility remodeling in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS), a model that simulates key features of human daily stressors. CUMS induced broad molecular reprogramming across hippocampal cell populations, with stress-responsive gene networks significantly enriched for depression-associated genes. The oligodendrocyte lineage showed heightened vulnerability, with CUMS preferentially disrupting immature OPC/intermediate states and impairing OPC migration, OPC-to-ODC lineage progression, intercellular communication, and myelination. Integrated multiomic analysis identified stage-specific cis-regulatory elements and stress-sensitive gene regulatory networks, converging on SOXD transcription factors, particularly SOX5 and SOX6, as key regulators of OPC dysfunction. SOX6 ChIP-seq confirmed direct SOX6 binding at regulatory elements associated with genes controlling OPC morphogenesis, migration, and glutamatergic signaling. CUMS reduced SOX6 protein levels and SOX6-associated regulatory network activity in OPCs, whereas OPC-specific enhancer-driven restoration of SOX6 rescued stress-induced defects in OPC migration and myelination. Together, these findings define a stress-sensitive SOXD/SOX6 regulatory mechanism linking chronic stress to oligodendrocyte lineage dysfunction and myelination deficits, identifying SOX6 as a functional regulatory node with therapeutic potential for stress-related brain pathology.

neuroscience↗

bioRxiv2025

Inherited retinal degenerations: PARP regulates calpain activation via TRPM2 channels in rd1 mouse photoreceptors

Inherited retinal degeneration (IRD) refers to untreatable blinding diseases characterized by progressive photoreceptor loss. Photoreceptor degeneration is often associated with an excessive activation of poly (ADP-ribose) polymerase (PARP) and Ca2+-dependent calpain-type proteases. To explore the interplay between PARP and calpain activity, we employed organotypic retinal explant cultures derived from wild-type mice and from the rd1 mouse model for IRD. Retinae were treated with the PARP inhibitors INO1001 or Olaparib, the poly (ADP-ribose) glycohydrolase (PARG) inhibitor JA2131, or the transient receptor potential channel M2 (TRPM2) blocker 8-Br-ADPR. Readouts included the TUNEL assay to detect cell death, in situ activity assays for histone-deacetylases (HDAC), PARP, and calpain, as well as immunostaining for activated calpain-2, and poly (ADP-ribose) (PAR). PARP, PARG, and TRPM2 inhibition reduced calpain activity and calpain-2 activation. PARP activity was decreased by PARP and TRPM2 inhibitors but not by PARG inhibition. Remarkably, the PARP inhibitor INO1001 increased HDAC activity unlike any of the other compounds. When combined with the PARG inhibitor JA2131, INO1001 reduced photoreceptor cell death in a synergistic fashion, although such synergy was not observed for calpain or PARP activity. Moreover, synergistic photoreceptor preservation was not observed when JA2131 was combined with the PARP inhibitor Olaparib. Overall, these results indicate that in rd1 photoreceptors, PARP controls calpain activity via PARG and TRPM2-induced Ca2+ influx. We also characterize INO1001 as potentially more beneficial for IRD treatment than Olaparib. Our study details the complexity of PARP-signalling in photoreceptors and identifies PARG and TRPM2 as new targets for IRD therapy development.

neuroscience↗

bioRxiv2025

PGC-1α and PPARs cooperatively mediate photoreceptor neuroprotection in rd1 mouse inherited retinal degeneration

Retinitis pigmentosa (RP) is a group of inherited diseases characterized by a primary rod photoreceptor dysfunction and progressive rod and cone cell death. Due to their very high energy demand, the degeneration of photoreceptors may be linked to insufficient energy supply or metabolic imbalance. Critical transcription factors that regulate metabolism such as peroxisome proliferator-activated receptors (PPARs) and their co-activator PGC-1 have been found to play important roles in neurodegenerative diseases, but their potential roles in RP have yet not been disclosed. In this study, we used organotypic retinal explant cultures derived from the rd1 mouse model for RP to investigate the effects of PPAR, PPAR{gamma}, PPAR{beta}/{delta} agonists, as well as PGC-1 activation and inhibition. Photoreceptor death in the outer nuclear layer (ONL) of the retina was quantified using the TUNEL assay, while in situ activity assays were used to monitor effects of PPARs and PGC-1 on poly (ADP-ribose) polymerase (PARP) and calpain activity. In addition, we performed immunostainings to evaluate poly (ADP-ribose) (PAR) generation and activation of calpain-1 and calpain-2. We found that PPAR{beta}/{delta} agonists had limited effects, while activation of PPAR, PPAR{gamma}, and PGC-1 significantly reduced photoreceptor death and PARP activity in rd1 retina. Conversely, inhibition of PGC-1 had a strong detrimental effect on photoreceptor viability. Activation of the histone deacetylase sirtuin-1, an upstream agonist of PGC-1, had no effect unless it was combined with simultaneous inhibition of PARP. Furthermore, PPAR{gamma} and PGC-1 effectively suppressed overall calpain activity and overactivation of calpain-2, alleviating photoreceptor degeneration caused by Ca2+ imbalance. In summary, our data supports the concept of a PARP-sirtuin-1-PGC-1-PPAR-PARP feedback control that connects defective energy metabolism to photoreceptor degeneration. Specifically, our findings suggest that PPAR, PPAR{gamma}, and PGC-1 cooperate to preserve photoreceptor viability, highlighting PPAR-signaling as a promising target for future therapeutic interventions.

neuroscience↗

bioRxiv2025

Resolving the estrogen paradox in hereditary retinal degeneration: Esr1 activation suppresses Tnf-α signaling as a photoreceptor self-protection mechanism

Retinitis pigmentosa (RP) is an inherited retinal degenerative disorder characterized by progressive photoreceptor loss and irreversible blindness. Increasing evidence implicates neuroinflammation as a contributor to photoreceptor degeneration extending beyond the initial genetic insult. Although estrogen has been reported to exert anti-inflammatory effects in the central nervous system, its role in RP remains controversial, with some studies suggesting a paradoxical exacerbation of retinal pathology. To address this discrepancy, we identify estrogen receptor alpha (Esr1) as a central immunoregulatory hub in RP. Transcriptomic analyses of rd1 and rd10 revealed upregulation of estrogen-responsive and inflammatory pathways, with Esr1 expression markedly elevated during degeneration. TUNEL assays demonstrated that systemic estradiol (E2) exerted divergent effects, protective in rd1 yet deleterious in rd10, whereas selective pharmacological activation of Esr1 with propyl pyrazole triol (PPT) consistently reduced photoreceptor death, preserved dark-adapted ERG responses, and downregulated inflammatory mediators including Tnf-, Cx3cl1/Cx3cr1, Cd68, and Iba1. Mechanistically, Esr1 activation repressed microglial Tnf transcription and disrupted a self-sustaining Cx3cl1/Cx3cr1-Tnf- signaling loop driving microglial recruitment, activation and neurotoxicity in the outer nuclear layer (ONL). Targeted interventions confirmed tumor necrosis factor receptor 1 (Tnfr1) as the principal mediator of Tnf-induced photoreceptor death: selective inhibition with R7050 conferred superior protection compared with broad-spectrum Tnf- inhibitors (etanercept, infliximab). Cx3cr1 blockade likewise suppressed microglial activation and improved visual outcomes. Collectively, our findings establish Esr1 activation as not merely an external intervention but the amplification of an intrinsic self-protective program, positioning Esr1, Tnfr1, and Cx3cr1 as actionable therapeutic targets to suppress neuroinflammation and preserve vision in RP and related retinal disorders.

neuroscience↗

bioRxiv2025

PARP activity is essential for retinal photoreceptor survival in the human homologous RhoI255del mouse model for autosomal dominant retinitis pigmentosa

Retinitis Pigmentosa (RP) is a group of rare, inherited, neurodegenerative diseases of the retina that primarily affect rod photoreceptors. The initial loss of rods is followed by a secondary cone photoreceptor degeneration and eventually legal blindness. Despite several attempts, RP still remains essentially untreatable. In recent years, inhibition of poly(ADP-ribose)polymerase (PARP) has been proposed as a potential therapeutic strategy of autosomal-recessive RP, based on promising work in preclinical animal models. However, the effects of PARP inhibitors in autosomal-dominant RP are still largely unknown. Here, we employed a novel, human-homologous rhodopsin-mutant RhoI255del/+ mouse model for autosomal dominant RP to assess the impact of different PARP inhibitors on the progression of photoreceptor degeneration. The PARP inhibitors used -olaparib, saruparib, INO1001, and nicotinamide- target different PARP isoforms, and their potentially differential effects were evaluated in organotypic retinal explants cultivated under entirely defined conditions. Readouts comprised in situ activity assays for PARP and calpain-type proteases, the TUNEL assay for cell death, as well as immunostaining for activated calpain-2, activated caspase-3, rhodopsin, and cone arrestin-3. Unexpectedly, and in contrast to previous findings in animal models for recessive RP, all of the included PARP inhibitors led to a marked and dose-dependent rod photoreceptor toxicity in the RhoI255del model for dominant RP. Furthermore, this effect appeared to be independent of rhodopsin expression. On the other hand, both cone photoreceptors and inner retinal neurons were apparently unaffected by PARP inhibition. The present study thus demonstrates the importance of PARP activity for rod photoreceptor viability in a dominant rhodopsin mutant, highlights the need for a deeper understanding of the mechanisms underlying photoreceptor degeneration in different RP forms, and cautions against the indiscriminate use of PARP inhibitors for the treatment of RP.

neuroscience↗

bioRxiv2025

Differential effects of HDAC inhibitors in the RhoI255d mouse model for autosomal dominant retinitis pigmentosa

Retinitis Pigmentosa (RP) is an inherited neurodegenerative disease which leads to loss of retinal photoreceptors and blindness. Histone deacetylases (HDAC) were previously found to be involved in photoreceptor cell death, and HDAC inhibitors have shown protective effects in animal models for autosomal recessive RP. However, whether HDAC inhibitors can protect photoreceptors in autosomal dominant RP (ADRP) remains unclear. Here, we utilized the recently generated human homologous RhoI255d/+ ADRP mouse model to investigate degenerative mechanisms and the therapeutic potential of HDAC inhibitors. To visualize photoreceptor HDAC activity, we applied an in situ HDAC activity assay on post-natal (P) day 20 wild type (WT) and RhoI255d/+ retina. Treatment with the HDAC class I/II inhibitor Trichostatin A and the HDAC class III inhibitor nicotinamide (NAM) suggested that most HDAC activity detected in RhoI255d/+ photoreceptors was related to class I/II isoforms. The therapeutic potential of different HDAC inhibitors, targeting different HDAC isoforms, was evaluated on organotypic retinal explants cultured under completely controlled conditions. HDAC inhibitors tested included SAHA (Vorinostat), MPT0G211, ACY-957, and NAM. Readouts comprised the TUNEL assay, immunostaining for activated calpain-2 and caspase-3, cone arrestin-3, and bromodeoxyuridine (BrdU)-labeling. Among the compounds tested, MPT0G211, targeting predominantly cytoplasmic HDAC-6, exhibited the strongest protective effect on both rod and cone photoreceptors. Remarkably, ACY-957, inhibiting nuclear HDAC-1/-2, at higher concentration induced both photoreceptor cell death and cell proliferation. High levels of NAM, blocking mitochondrial and nuclear HDACs, caused selective rod cell death, without affecting cones. All HDAC inhibitors tested had no or only minor effects on neurons of the inner retina. Our study highlights the complexity of HDAC activity during photoreceptor neurodegeneration and cautions against the use of unspecific inhibitors. At the same time, it showcases important differences between rod and cone photoreceptors and suggests especially HDAC-6 as a potential target for future therapy development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/666875v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@598681org.highwire.dtl.DTLVardef@18d8ba4org.highwire.dtl.DTLVardef@1cacb24org.highwire.dtl.DTLVardef@dec519_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Inherited retinal degeneration: T-type voltage-gated channels, Na+/Ca2+-exchanger, and calpain-2 promote photoreceptor cell death.

Inherited retinal degeneration (IRD) refers to a group of untreatable blinding diseases characterized by a progressive loss of photoreceptors. IRD pathology is often linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na+- and Ca2+-influx, subsequent activation of voltage-gated Ca2+-channels (VGCC), and further Ca2+ influx. However, whether and how exactly intracellular Ca2+ overload contributes to photoreceptor degeneration is still controversial. Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the rd1 mouse model for IRD and wild-type (wt) mice. Differentially expressed genes were linked to several Ca2+-signalling related pathways. To explore this further, organotypic retinal explant cultures derived from rd1 and wt mice were treated with the intracellular Ca2+-chelator BAPTA-AM and with inhibitors for different Ca2+-permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca2+-release-activated channel (CRAC), and Na+/Ca2+ exchanger (NCX). Moreover, we employed the compound NA-184 to selectively inhibit the Ca2+-dependent protease calpain-2. The overall activity of poly(ADP-ribose) polymerases (PARPs), sirtuin-type histone-deacetylases, calpains, as well as the activation of calpain-1, and -2 were analysed in situ on retinal tissue sections. Cell viability was assessed via the TUNEL assay. While rd1 photoreceptor cell death was reduced by BAPTA-AM, the effects of Ca2+-channel blockers were ambiguous, with T-type VGCC and NCX inhibition showing protection, while blocking CNGC and CRAC was detrimental. Activity of calpains and PARPs generally followed similar trends as cell death. Remarkably, sirtuin activity and calpain-1 activation was associated with photoreceptor protection, while calpain-2 activity was linked to degeneration. Accordingly, the calpain-2 inhibitor NA-184 protected rd1 photoreceptors. Together, these results indicate that Ca2+ overload in rd1 photoreceptors may be triggered by T-type VGCC in conjunction with NCX. High Ca2+-levels likely suppress the protective activity of calpain-1 and promote neurodegeneration via activation of calpain-2. Our study details the complexity of Ca2+-signalling in photoreceptors and emphasizes the importance of identifying and targeting degenerative processes to achieve a therapeutic benefit for IRD.

neuroscience↗

bioRxiv2022

A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene

Sick sinus syndrome (SSS) is a group of heart rhythm disorders caused by malfunction of the sinus node, the hearts primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. Here, we aim to develop a phenotype-based forward genetic approach in the zebrafish (Danio rerio) animal model for discovering essential genes which dysfunction could result in SSS-like phenotypes. Previously we showed the generation of protein trap library by using a revertible gene-breaking transposon (GBT)-based insertional mutagenesis system. Here, we reported the generation of a collection of 35 zebrafish insertional cardiac lines derived from this protein trap library, which was screened using electrocardiographic measurements. As a result, three mutants with SSS-like phenotypes were identified. We then focused on one of these 3 GBT mutants called GBT411 in which dnajb6b gene was disrupted, and conducted expressional, genetic, transcriptome, and electrophysiological studies using both zebrafish and mouse models. These studies confirmed the identity of Dnajb6 as a novel SSS causative gene with a unique expression pattern within the specialized population of sinus node pacemaker cardiomyocytes that lack the expression of HCN4 channels. Together, this study demonstrates the feasibility of a genetic screening approach in an adult vertebrate animal model for discovering new genetic factors for a heart rhythm disorder such as SSS.

genetics↗

bioRxiv2022

Differential Requirement of DICER1 Activity during Development of Mitral and Tricuspid Valves

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivated Dicer1 in the endocardium during cardiogenesis, and unexpectedly found that Dicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically. Summary statementAlthough mitral and tricuspid heart valves are both derived from same cell sources in the atrioventricular region through similar initiation and remodeling processes, congenital dysplasia simultaneously affecting both valves is clinically uncommon. We show that DICER1 activity is only essential for mitral valve development whereas it is dispensable for other valves. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that is differentially required to regulate mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.

developmental biology↗

bioRxiv2021

Mitochondrial Fission Regulates Transcription of Ribosomal Protein Genes in Embryonic Hearts

Mitochondrial dysfunction causes severe congenital heart diseases and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target inborn heart defects due to mitochondrial deficiency. Mitochondrial morphology, which is regulated by fission and fusion, plays key roles in determining mitochondrial activity. Drp1 encodes a dynamin-related GTPase required for mitochondrial fission. To investigate the role of mitochondrial fission on cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Drp1 in second heart field derived structures. Deletion of Drp1 in embryonic cardiomyocytes led to severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the mitochondrial fission anomaly to reduced transcription of ribosomal protein genes in mutant cardiomyocytes. We therefore provide the first mouse genetic evidence to show that mitochondrial fission is essential for embryonic heart development. Furthermore, we uncovered a novel signaling cascade that mediates the crosstalk between mitochondrial dysfunction and protein synthesis. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.

developmental biology↗

bioRxiv2019

SORBS2 is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

BACKGROUNDArrhythogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular remodeling and ventricular arrhythmia. To date, 16 ARVC causative genes have been identified from human genetic studies, accounting for about 60% of ARVC probands. Genetic basis for the remaining 40% ARVC probands remain elusive.\n\nMETHODSPrompted by a zebrafish mutagenesis screen that suggested the Sorbin and SH3 domain-containing 2 (SORBS2) ortholog as a candidate cardiomyopathy gene, we conducted detailed expressionl analysis of Sorbs2 in mice, as well as phenotypic characterization in the Sorbs2 knock-out (KO) mice. The intercalated disc (ICD) expression pattern and ARVC-like phenotypes further prompted us to conduct targeted sequencing of human patients with ARVC to search for rare variants in the SORBS2 gene.\n\nRESULTSSorbs2 is robustly expressed in the mouse heart, encoding an adhesion junction/desmosome protein that is mainly localized to the ICD. A mutation with near complete depletion of the Sorbs2 protein in mouse results in phenotypes characteristic of human ARVC, such as dilated right ventricle (RV), RV dysfunction, spontaneous ventricular tachycardia (VT), and premature death. Sorbs2 is required to maintain the structural integrity of ICD. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Five rare variants were identified from a cohort of 59 ARVC patients, among which two variants affect splicing.\n\nCONCLUSIONSSorbs2 KO mouse is an ARVC model and SORBS2 is a new ARVC susceptibility gene.

genetics↗