Primary cilia direct murine articular cartilage tidemark patterning through Hedgehog signaling and ambulatory load

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2022 Jan 21

Rux, D;Helbig, K;Han, B;Cortese, C;Koyama, E;Han, L;Pacifici, M;
PMID: 35060644 | DOI: 10.1002/jbmr.4506

Articular cartilage (AC) is essential for body movement but is highly susceptible to degenerative diseases and has poor self-repair capacity. To improve current subpar regenerative treatments, developmental mechanisms of AC should be clarified and, specifically, how its postnatal multi-zone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis. While their importance for chondrocyte functioning is appreciated, their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss-of-function approach (Ift88-flox) targeting joint-lineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected. However, mature AC (aged 2 months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30-50%. In addition, and unexpectedly, we discovered that tidemark patterning was severely disrupted, as was hedgehog signaling, and exhibited specificity based on regional load-bearing functions of AC. Interestingly, Prg4 expression was markedly increased in highly loaded sites in mutants. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis including tidemark topography, zonal matrix composition and ambulation load responses. This article is protected by

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

International journal of molecular sciences

2022 Jan 16

Troadec, JD;Gaigé, S;Barbot, M;Lebrun, B;Barbouche, R;Abysique, A;
PMID: 35055143 | DOI: 10.3390/ijms23020960

The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level.

Identification of Lung Innervating Sensory Neurons and Their Target Specificity

American journal of physiology. Lung cellular and molecular physiology

2021 Nov 10

Su, Y;Barr, J;Jaquish, A;Xu, J;Verheyden, JM;Sun, X;
PMID: 34755535 | DOI: 10.1152/ajplung.00376.2021

Known as the gas exchange organ, the lung is also critical for responding to the aerosol environment in part through interaction with the nervous system. The diversity and specificity of lung innervating neurons remains poorly understood. Here, we interrogated the cell body location, molecular signature and projection pattern of lung innervating sensory neurons. Retrograde tracing from the lung coupled with whole tissue clearing highlighted neurons primarily in the vagal ganglia. Centrally, they project specifically to the nucleus of the solitary tract in the brainstem. Peripherally, they enter the lung alongside branching airways. Labeling of nociceptor Trpv1+ versus peptidergic Tac1+ vagal neurons showed shared and distinct terminal morphology and targeting to airway smooth muscles, vasculature including lymphatics, and alveoli. Notably, a small population of vagal neurons that are Calb1+ preferentially innervate pulmonary neuroendocrine cells, a demonstrated airway sensor population. This atlas of lung innervating neurons serves as a foundation for understanding their function in lung.

Neuropathogenesis of severe acute respiratory syndrome coronavirus 2

Current opinion in pediatrics

2021 Dec 01

Patel, PB;Bearden, D;
PMID: 34734914 | DOI: 10.1097/MOP.0000000000001068

The purpose of this review is to address our current understanding of the pathophysiology of neurologic injury resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection on the developing nervous system.SARS-CoV2 may enter the brain through three potential mechanisms: transsynaptic spread from the olfactory bulb following intranasal exposure, migration across the blood-brain barrier through endothelial cell infection, and migration following disruption of the blood-brain barrier from resulting inflammation. SARS-CoV2 does not appear to directly infect neurons but rather may produce an inflammatory cascade that results in neuronal injury. Additionally, autoantibodies targeting neuronal tissue resulting from the immune response to SARS-CoV2 are present in select patients and may contribute to central nervous system (CNS) injury.These findings suggest that neuronal injury during SARS-CoV2 infection is immune mediated rather than through direct viral invasion. Further multimodal studies evaluating the pathophysiology of neurologic conditions in pediatric patients specifically following SARS-CoV2 infection are needed to improve our understanding of mechanisms driving neurologic injury and to identify potential treatment options.

Hippocampal BMP signaling as a common pathway for antidepressant action

Cellular and molecular life sciences : CMLS

2021 Dec 22

Tunc-Ozcan, E;Brooker, SM;Bonds, JA;Tsai, YH;Rawat, R;McGuire, TL;Peng, CY;Kessler, JA;
PMID: 34936033 | DOI: 10.1007/s00018-021-04026-y

The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy. All of these therapies decrease BMP signaling and enhance neurogenesis in the hippocampus. Preventing the decrease in BMP signaling blocks the effect of antidepressant treatment on behavioral phenotypes. Further, inhibition of BMP signaling in hippocampal newborn neurons is sufficient to produce an antidepressant effect, while chemogenetic silencing of newborn neurons prevents the antidepressant effect. Thus, inhibition of hippocampal BMP signaling is both necessary and sufficient to mediate the effects of multiple classes of antidepressants.

Topical application of cannabinoid-ligands ameliorates experimental dry-eye disease

The ocular surface

2021 Dec 16

Tran, BN;Maass, M;Musial, G;Stern, ME;Gehlsen, U;Steven, P;
PMID: 34922011 | DOI: 10.1016/j.jtos.2021.12.008

Dry eye disease (DED) is a multifactorial disease, with limitations regarding efficacy and tolerability of applied substances. Among several candidates, the endocannabinoid system with its receptors (CB1R and CB2R) were reported to modulate inflammation, wound healing and pain, which are also core DED pathomechanisms. This study is to investigate the therapeutic responses of Δ-9 tetrahydrocannabinol (a non-selective agonist) and two selective antagonists, SR141716A (CB1R antagonist) and SR144528 (CB2R antagonist), as a topical application using a DED mouse model.Experimental DED was induced in naïve C57BL/6 mice. Expression of CBR at the ocular surface of naïve and DED mice was determined by qPCR and in-situ hybridization. Either THC or CBR antagonists were compounded in an aqueous solution and dosed during the induction of DED. Tear production, cornea sensitivity, and cornea fluorescence staining were tested. At the end of each experiment, corneas were stained with β3-tubulin for analysis of corneal nerve morphology. Conjunctiva was analyzed for CD4+ and CD8+ infiltration.CB1R and CB2R are present at the ocular surface, and desiccating stress increased CBR expressions (p < 0.05). After 10 days of DED induction, treated groups demonstrated a reduced CBR expression in the cornea, which was concurrent with improvements in the DED phenotype including fluorescence staining & inflammation. Applying THC protected corneal nerve morphology, thus maintained corneal sensitivity and reduced CD4+ T-cell infiltration. The CB1R antagonist maintained cornea sensitivity without changing nerve morphology.Endocannabinoid receptor modulation presents a potential multi-functional therapeutic approach for DED.

Relationship between Serum Elabela Level and Hypertensıve Nephropathy

Journal of the College of Physicians and Surgeons--Pakistan : JCPSP

2021 Dec 01

Dogan, Y;Onalan, E;Cavli, C;Onalan, EE;Yakar, B;Donder, E;
PMID: 34794279 | DOI: 10.29271/jcpsp.2021.12.1412

To determine the difference in serum Elabela level in hypertensive patients with and without nephropathy compared to the healthy control group. Study Desing: Cross-sectional descriptive study.Fırat University Medical School, Elazig, Turkey between December 2018 and November 2020.The cross-sectional descriptive study consisted of 37 patients with hypertensive nephropathy (group 3), 50 hypertensive patients without nephropathy (group 2), and 50 healthy controls (group 1). Hypertensive nephropathy was defined as serum creatinine ≥1.8 mg / dl or GFR <40 ml / minute. Biochemical parameters (Glucose, AST, ALT, urea, creatinine, lipid levels, hemogram, calcium, phosphorus, parathormone) and the levels of serum Elabela were evaluated and compared.There was no significant difference in age (0.270) and gender (0.951) between groups. The median Elabela levels of the three groups were 40.3 ng/mL (22.5-54.6), 5.1 ng/mL (3.7-8.3), 9.2 ng/mL (6.1-23.1), respectively with a significant difference (p<0.001).The plasma levels of Elabela were lower in the case of hypertension, independent of nephropathy. However, this decrease is not specific for nephropathy and may be due to other accompanying chronic diseases. Key Words: Hypertension, Hypertensive nephropathy, Elabela.

Cell geometry, signal dampening, and a bimodal transcriptional response underlie the spatial precision of an ERK-mediated embryonic induction

Developmental cell

2021 Oct 16

Williaume, G;de Buyl, S;Sirour, C;Haupaix, N;Bettoni, R;Imai, KS;Satou, Y;Dupont, G;Hudson, C;Yasuo, H;
PMID: 34672970 | DOI: 10.1016/j.devcel.2021.09.025

Precise control of lineage segregation is critical for the development of multicellular organisms, but our quantitative understanding of how variable signaling inputs are integrated to activate lineage-specific gene programs remains limited. Here, we show how precisely two out of eight ectoderm cells adopt neural fates in response to ephrin and FGF signals during ascidian neural induction. In each ectoderm cell, FGF signals activate ERK to a level that mirrors its cell contact surface with FGF-expressing mesendoderm cells. This gradual interpretation of FGF inputs is followed by a bimodal transcriptional response of the immediate early gene, Otx, resulting in its activation specifically in the neural precursors. At low levels of ERK, Otx is repressed by an ETS family transcriptional repressor, ERF2. Ephrin signals are critical for dampening ERK activation levels across ectoderm cells so that only neural precursors exhibit above-threshold levels, evade ERF repression, and "switch on" Otx transcription.

Mu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2021 Sep 30

Han, J;Andreu, V;Langreck, C;Pekarskaya, EA;Grinnell, SG;Allain, F;Magalong, V;Pintar, J;Kieffer, BL;Harris, AZ;Javitch, JA;Hen, R;Nautiyal, KM;
PMID: 34593976 | DOI: 10.1038/s41386-021-01192-2

Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. Thus, our studies aim to understand the neural circuits underlying tianeptine's antidepressant effects. We show that tianeptine induces rapid antidepressant-like effects in mice after as little as one week of treatment. Critically, we also demonstrate that tianeptine's mechanism of action is distinct from fluoxetine in two important aspects: (1) tianeptine requires MORs for its chronic antidepressant-like effect, while fluoxetine does not, and (2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis. Using cell-type specific MOR knockouts we further show that MOR expression on GABAergic cells-specifically somatostatin-positive neurons-is necessary for the acute and chronic antidepressant-like responses to tianeptine. Using central infusion of tianeptine, we also implicate the ventral hippocampus as a potential site of antidepressant action. Moreover, we show a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.

The noncoding genome and hearing loss

Human genetics

2021 Sep 07

Avraham, KB;Khalaily, L;Noy, Y;Kamal, L;Koffler-Brill, T;Taiber, S;
PMID: 34491412 | DOI: 10.1007/s00439-021-02359-z

The age of sequencing has provided unprecedented insights into the human genome. The coding region of the genome comprises nearly 20,000 genes, of which approximately 4000 are associated with human disease. Beyond the protein-coding genome, which accounts for only 3% of the genome, lies a vast pool of regulatory elements in the form of promoters, enhancers, RNA species, and other intricate elements. These features undoubtably influence human health and disease, and as a result, a great deal of effort is currently being invested in deciphering their identity and mechanism. While a paucity of material has caused a lag in identifying these elements in the inner ear, the emergence of technologies for dealing with a minimal number of cells now has the field working overtime to catch up. Studies on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), methylation, histone modifications, and more are ongoing. A number of microRNAs and other noncoding elements are known to be associated with hearing impairment and there is promise that regulatory elements will serve as future tools and targets of therapeutics and diagnostics. This review covers the current state of the field and considers future directions for the noncoding genome and implications for hearing loss.

Spatial mapping of the tumor immune microenvironment

Engineering Technologies and Clinical Translation

2021 Sep 03

Wu, Y;Pagacz, J;Emery, S;Kron, S;Lee, S;
| DOI: 10.1016/B978-0-323-90949-5.00009-7

To replace one-size-fits-all cancer immunotherapy with personalized treatment, biomarkers of response and resistance as well as assays to evaluate them in each patient are essential. Among likely determinants of response, the spatial locations and activation states of the immune infiltrate appear critical. Current clinical methods for tissue analysis such as immunohistochemistry are poorly matched to the heterogeneity of the tumor immune microenvironment (TIME). However, multiple tools for analysis of the TIME can now image panels of biomarkers in a single experiment, permit deep profiling to measure dozens of immune features in each sample, and/or facilitate unbiased multiomic analysis at high spatial resolution. Several assays are commercialized with some nearing clinical adoption. In this chapter, we present a broad overview of established and emerging technologies that enable multiplexed detection and spatial mapping of cellular and molecular features of the TIME, highlighting advantages and disadvantages as well as opportunities for future development.

Using single-nucleus RNA-sequencing to interrogate transcriptomic profiles of archived human pancreatic islets

Genome medicine

2021 Aug 10

Basile, G;Kahraman, S;Dirice, E;Pan, H;Dreyfuss, JM;Kulkarni, RN;
PMID: 34376240 | DOI: 10.1186/s13073-021-00941-8

Human pancreatic islets are a central focus of research in metabolic studies. Transcriptomics is frequently used to interrogate alterations in cultured human islet cells using single-cell RNA-sequencing (scRNA-seq). We introduce single-nucleus RNA-sequencing (snRNA-seq) as an alternative approach for investigating transplanted human islets.The Nuclei EZ protocol was used to obtain nuclear preparations from fresh and frozen human islet cells. Such preparations were first used to generate snRNA-seq datasets and compared to scRNA-seq output obtained from cells from the same donor. Finally, we employed snRNA-seq to obtain the transcriptomic profile of archived human islets engrafted in immunodeficient animals.We observed virtually complete concordance in identifying cell types and gene proportions as well as a strong association of global and islet cell type gene signatures between scRNA-seq and snRNA-seq applied to fresh and frozen cultured or transplanted human islet samples.We propose snRNA-seq as a reliable strategy to probe transcriptomic profiles of freshly harvested or frozen sources of transplanted human islet cells especially when scRNA-seq is not ideal.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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