Molecular identity of proprioceptor subtypes innervating different muscle groups in mice

Nature communications

2022 Nov 11

Dietrich, S;Company, C;Song, K;Lowenstein, ED;Riedel, L;Birchmeier, C;Gargiulo, G;Zampieri, N;
PMID: 36369193 | DOI: 10.1038/s41467-022-34589-8

The precise execution of coordinated movements depends on proprioception, the sense of body position in space. However, the molecular underpinnings of proprioceptive neuron subtype identities are not fully understood. Here we used a single-cell transcriptomic approach to define mouse proprioceptor subtypes according to the identity of the muscle they innervate. We identified and validated molecular signatures associated with proprioceptors innervating back (Tox, Epha3), abdominal (C1ql2), and hindlimb (Gabrg1, Efna5) muscles. We also found that proprioceptor muscle identity precedes acquisition of receptor character and comprise programs controlling wiring specificity. These findings indicate that muscle-type identity is a fundamental aspect of proprioceptor subtype differentiation that is acquired during early development and includes molecular programs involved in the control of muscle target specificity.

T028: Single-cell RNA sequencing reveals the interplay between circulating CD4 T cells, B cells and cancer-associated monocytes in classic Hodgkin lymphoma treated with PD-1 blockade

HemaSphere

2022 Oct 03

Paczkowska, J;Tang, M;Wright, K;Song, L;Shanmugam, V;Luu, K;Welsh, E;Cader, F;Mandato, E;Ouyang, J;Bai, G;Lawton, L;Rodig, S;Liu, X;Shipp, M;
| DOI: 10.1097/01.hs9.0000890680.82329.6b

The most abundant circulating CD3- population in patients with cHL was a newly identified monocyte subset with increased expression of multiple immunosuppressive and tumorigenic cytokines and chemokines, PD-L1 and SIRPa. This newly identified monocytic population was virtually absent from the blood of healthy donors. RNAscope analysis of the intact tumor microenvironment localized these tumor-infiltrating monocytes/macrophages to the immediate proximity of HRS cells. Monocytes from patients whose disease progressed following PD-1 blockade expressed significantly higher levels of immunosuppressive cytokine/chemokine signature which led to the development of a predictive transcriptional assay. We identified a comparable circulating monocyte population and transcriptional signature associated with unresponsiveness to PD-1 blockade in an additional solid tumor underscoring the broad-based significance of these findings.

Gene Expression Signatures of the Tumor Microenvironment: Relation to Tumor Phenotypes and Progress in Breast Cancer

Biomarkers of the Tumor Microenvironment

2022 Jul 13

Wik, E;Ingebriktsen, L;Akslen, L;
| DOI: 10.1007/978-3-030-98950-7_23

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Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection

Molecular medicine (Cambridge, Mass.)

2021 Dec 27

Chapoval, SP;Keegan, AD;
PMID: 34961486 | DOI: 10.1186/s10020-021-00423-y

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike-NRP1 interaction to combat virus infectivity and severe disease manifestations.

Ribosomal Pulldown Assays and Their Use to Analyze Gene Expression in Multiple Inner Ear Cell Types

Neuromethods

2022 Jan 01

Matern, M;Milon, B;Elkon, R;Hertzano, R;
| DOI: 10.1007/978-1-0716-2022-9_8

A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose

Neuron

2021 Aug 25

Amin, ND;Senturk, G;Costaguta, G;Driscoll, S;O'Leary, B;Bonanomi, D;Pfaff, SL;
PMID: 34450025 | DOI: 10.1016/j.neuron.2021.07.028

Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA's in vivo abundance (rather than its binary gain or loss) are not well understood. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-selective gene regulator associated with motor neuron disease. Titration of miR-218 cellular dose unexpectedly revealed complex, non-ratiometric target mRNA dose responses and distinct gene network outputs. A non-linearly responsive regulon exhibited a steep miR-218 dose-dependent threshold in repression that, when crossed, resulted in severe motor neuron synaptic failure and death. This work demonstrates that a miRNA can govern distinct gene network outputs at different expression levels and that miRNA-dependent phenotypes emerge at particular dose ranges because of hidden regulatory inflection points of their underlying gene networks.

Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

Cancer cell

2021 Jun 14

Hara, T;Chanoch-Myers, R;Mathewson, ND;Myskiw, C;Atta, L;Bussema, L;Eichhorn, SW;Greenwald, AC;Kinker, GS;Rodman, C;Gonzalez Castro, LN;Wakimoto, H;Rozenblatt-Rosen, O;Zhuang, X;Fan, J;Hunter, T;Verma, IM;Wucherpfennig, KW;Regev, A;Suvà, ML;Tirosh, I;
PMID: 34087162 | DOI: 10.1016/j.ccell.2021.05.002

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.

Bridging scales: From cell biology to physiology using in situ single-cell technologies

Cell systems

2021 May 19

Nagle, MP;Tam, GS;Maltz, E;Hemminger, Z;Wollman, R;
PMID: 34015260 | DOI: 10.1016/j.cels.2021.03.002

Biological organization crosses multiple spatial scales: from molecular, cellular, to tissues and organs. The proliferation of molecular profiling technologies enables increasingly detailed cataloging of the components at each scale. However, the scarcity of spatial profiling has made it challenging to bridge across these scales. Emerging technologies based on highly multiplexed in situ profiling are paving the way to study the spatial organization of cells and tissues in greater detail. These new technologies provide the data needed to cross the scale from cell biology to physiology and identify the fundamental principles that govern tissue organization. Here, we provide an overview of these key technologies and discuss the current and future insights these powerful techniques enable.

Novel Tyrosine Kinase Targets in Urothelial Carcinoma

International journal of molecular sciences

2021 Jan 13

Torres-Jiménez, J;Albarrán-Fernández, V;Pozas, J;Román-Gil, MS;Esteban-Villarrubia, J;Carrato, A;Rosero, A;Grande, E;Alonso-Gordoa, T;Molina-Cerrillo, J;
PMID: 33451055 | DOI: 10.3390/ijms22020747

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.

Coordination between Transport and Local Translation in Neurons

Trends in Cell Biology

2021 Jan 01

Broix, L;Turchetto, S;Nguyen, L;
| DOI: 10.1016/j.tcb.2021.01.001

The axonal microtubules (MTs) support long-distance transport of cargoes that are dispatched to distinct cellular subcompartments. Among them, mRNAs are directly transported in membraneless ribonucleoprotein (RNP) granules that, together with ribosomes, can also hitchhike on fast-moving membrane-bound organelles for accurate transport along MTs. These organelles serve as platforms for mRNA translation, thus generating axonal foci of newly synthesized proteins. Local translation along axons not only supports MT network integrity but also modulates the processivity and function of molecular motors to allow proper trafficking of cargoes along MTs. Thus, identifying the mechanisms that coordinate axonal transport with local protein synthesis will shed new light on the processes underlying axon development and maintenance, whose deregulation often contribute to neurological disorders.

Analysis of mitochondrial double-stranded RNAs in human cells

STAR Protocols

2023 Mar 01

Kim, S;Yoon, J;Lee, K;Kim, Y;
| DOI: 10.1016/j.xpro.2022.102007

Human mitochondrial genome is transcribed bidirectionally, generating long complementary RNAs that can form double-stranded RNAs (mt-dsRNAs). When released to the cytosol, these mt-dsRNAs can activate antiviral signaling. Here, we present a detailed protocol for the analysis of mt-dsRNA expression. The protocol provides three approaches that can complement one another in examining mt-dsRNAs. While the described protocol is optimized for human cells, this approach can be adapted for use in other animal cell lines and tissue samples. For complete details on the use and execution of this protocol, please refer to Kim et al. (2022).1

Transgenic Mouse Models to Study the Development and Maintenance of the Adrenal Cortex

International journal of molecular sciences

2022 Nov 19

Abou Nader, N;Zamberlam, G;Boyer, A;
PMID: 36430866 | DOI: 10.3390/ijms232214388

The cortex of the adrenal gland is organized into concentric zones that produce distinct steroid hormones essential for body homeostasis in mammals. Mechanisms leading to the development, zonation and maintenance of the adrenal cortex are complex and have been studied since the 1800s. However, the advent of genetic manipulation and transgenic mouse models over the past 30 years has revolutionized our understanding of these mechanisms. This review lists and details the distinct Cre recombinase mouse strains available to study the adrenal cortex, and the remarkable progress total and conditional knockout mouse models have enabled us to make in our understanding of the molecular mechanisms regulating the development and maintenance of the adrenal cortex.

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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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