Independent Skeletal Actions of Pituitary Hormones

Endocrinology and metabolism (Seoul, Korea)

2022 Oct 01

Kim, SM;Sultana, F;Korkmaz, F;Lizneva, D;Yuen, T;Zaidi, M;
PMID: 36168775 | DOI: 10.3803/EnM.2022.1573

Over the past years, pituitary hormones and their receptors have been shown to have non-traditional actions that allow them to bypass the hypothalamus-pituitary-effector glands axis. Bone cells-osteoblasts and osteoclasts-express receptors for growth hormone, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin, and vasopressin. Independent skeletal actions of pituitary hormones on bone have been studied using genetically modified mice with haploinsufficiency and by activating or inactivating the receptors pharmacologically, without altering systemic effector hormone levels. On another front, the discovery of a TSH variant (TSH-βv) in immune cells in the bone marrow and skeletal action of FSHβ through tumor necrosis factor α provides new insights underscoring the integrated physiology of bone-immune-endocrine axis. Here we discuss the interaction of each pituitary hormone with bone and the potential it holds in understanding bone physiology and as a therapeutic target.

Pangenomic analysis of Chinese gastric cancer

Nature communications

2022 Sep 15

Yu, Y;Zhang, Z;Dong, X;Yang, R;Duan, Z;Xiang, Z;Li, J;Li, G;Yan, F;Xue, H;Jiao, D;Lu, J;Lu, H;Zhang, W;Wei, Y;Fan, S;Li, J;Jia, J;Zhang, J;Ji, J;Liu, P;Lu, H;Zhao, H;Chen, S;Wei, C;Chen, H;Zhu, Z;
PMID: 36109518 | DOI: 10.1038/s41467-022-33073-7

Pangenomic study might improve the completeness of human reference genome (GRCh38) and promote precision medicine. Here, we use an automated pipeline of human pangenomic analysis to build gastric cancer pan-genome for 185 paired deep sequencing data (370 samples), and characterize the gene presence-absence variations (PAVs) at whole genome level. Genes ACOT1, GSTM1, SIGLEC14 and UGT2B17 are identified as highly absent genes in gastric cancer population. A set of genes from unaligned sequences with GRCh38 are predicted. We successfully locate one of predicted genes GC0643 on chromosome 9q34.2. Overexpression of GC0643 significantly inhibits cell growth, cell migration and invasion, cell cycle progression, and induces cell apoptosis in cancer cells. The tumor suppressor functions can be reversed by shGC0643 knockdown. The GC0643 is approved by NCBI database (GenBank: MW194843.1). Collectively, the robust pan-genome strategy provides a deeper understanding of the gene PAVs in the human cancer genome.

Condyloma and coincidental epidermodysplasia verruciformis acanthoma positive for human papillomavirus-14 and-21

Journal of cutaneous pathology

2022 Aug 30

Bartley, B;Cho, WC;Rady, PL;Dai, J;Curry, JL;Milbourne, A;Tyring, SK;Torres-Cabala, CA;
PMID: 36039682 | DOI: 10.1111/cup.14319

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes individuals to persistent infection with β-human papillomavirus (HPV) genotypes. The term EDV acanthoma may be applied to lesions with incidental findings of EDV-defining histopathological features without clinical signs of EDV. We report a case of HPV-14- and -21-positive EDV acanthoma arising in association with condyloma in a female patient with a history of low-grade squamous intraepithelial lesion of the cervix positive for high-risk HPV (non-16/18), chronic kidney disease, and systemic lupus erythematosus. The patient had no family or personal history of EDV, but the patient was on immunosuppressive therapy with mycophenolate mofetil and prednisone. A biopsy specimen from one of the perianal lesions revealed histopathologic changes consistent with EDV in the setting of condyloma. Molecular testing showed HPV-14 and -21, which supported the coexistence of condyloma with EDV acanthoma.

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

The Journal of experimental medicine

2022 Sep 05

Kaiser, FMP;Gruenbacher, S;Oyaga, MR;Nio, E;Jaritz, M;Sun, Q;van der Zwaag, W;Kreidl, E;Zopf, LM;Dalm, VASH;Pel, J;Gaiser, C;van der Vliet, R;Wahl, L;Rietman, A;Hill, L;Leca, I;Driessen, G;Laffeber, C;Brooks, A;Katsikis, PD;Lebbink, JHG;Tachibana, K;van der Burg, M;De Zeeuw, CI;Badura, A;Busslinger, M;
PMID: 35947077 | DOI: 10.1084/jem.20220498

The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.

Lentiviral Vectors for Ocular Gene Therapy

Pharmaceutics

2022 Jul 31

Arsenijevic, Y;Berger, A;Udry, F;Kostic, C;
PMID: 36015231 | DOI: 10.3390/pharmaceutics14081605

This review offers the basics of lentiviral vector technologies, their advantages and pitfalls, and an overview of their use in the field of ophthalmology. First, the description of the global challenges encountered to develop safe and efficient lentiviral recombinant vectors for clinical application is provided. The risks and the measures taken to minimize secondary effects as well as new strategies using these vectors are also discussed. This review then focuses on lentiviral vectors specifically designed for ocular therapy and goes over preclinical and clinical studies describing their safety and efficacy. A therapeutic approach using lentiviral vector-mediated gene therapy is currently being developed for many ocular diseases, e.g., aged-related macular degeneration, retinopathy of prematurity, inherited retinal dystrophies (Leber congenital amaurosis type 2, Stargardt disease, Usher syndrome), glaucoma, and corneal fibrosis or engraftment rejection. In summary, this review shows how lentiviral vectors offer an interesting alternative for gene therapy in all ocular compartments.

GPR15L is an epithelial inflammation-derived pruritogen

Science advances

2022 Jun 17

Tseng, PY;Hoon, MA;
PMID: 35704588 | DOI: 10.1126/sciadv.abm7342

Itch is an unpleasant sensation that often accompanies chronic dermatological conditions. Although many of the itch receptors and the neural pathways underlying this sensation are known, the identity of endogenous ligands is still not fully appreciated. Using an unbiased bioinformatic approach, we identified GPR15L as a candidate pruritogen whose expression is robustly up-regulated in psoriasis and atopic dermatitis. Although GPR15L was previously shown to be a cognate ligand of the receptor GPR15, expressed in dermal T cells, here we show that it also contributes to pruritogenesis by activating Mas-related G protein-coupled receptors (MRGPRs). GPR15L can selectively stimulate mouse dorsal root ganglion neurons that express Mrgpra3 and evokes intense itch responses. GPR15L causes mast cell degranulation through stimulation of MRGPRX2 and Mrgprb2. Genetic disruption of GPR15L expression attenuates scratch responses in a mouse model of psoriasis. Our study reveals unrecognized features of GRP15L, showing that it is a potent itch-inducing agent.

Transcription activation is enhanced by multivalent interactions independent of phase separation

Molecular cell

2022 May 19

Trojanowski, J;Frank, L;Rademacher, A;Mücke, N;Grigaitis, P;Rippe, K;
PMID: 35537448 | DOI: 10.1016/j.molcel.2022.04.017

Transcription factors (TFs) consist of a DNA-binding domain and an activation domain (AD) that are frequently considered to be independent and exchangeable modules. However, recent studies report that the physicochemical properties of the AD can control TF assembly at chromatin by driving phase separation into transcriptional condensates. Here, we dissected transcription activation by comparing different synthetic TFs at a reporter gene array with real-time single-cell fluorescence microscopy. In these experiments, binding site occupancy, residence time, and coactivator recruitment in relation to multivalent TF interactions were compared. While phase separation propensity and activation strength of the AD were linked, the actual formation of liquid-like TF droplets had a neutral or inhibitory effect on transcription activation. We conclude that multivalent AD-mediated interactions enhance the transcription activation capacity of a TF by increasing its residence time in the chromatin-bound state and facilitating the recruitment of coactivators independent of phase separation.

A novel spinal neuron connection for heat sensation

Neuron

2022 May 06

Wang, H;Chen, W;Dong, Z;Xing, G;Cui, W;Yao, L;Zou, WJ;Robinson, HL;Bian, Y;Liu, Z;Zhao, K;Luo, B;Gao, N;Zhang, H;Ren, X;Yu, Z;Meixiong, J;Xiong, WC;Mei, L;
PMID: 35561677 | DOI: 10.1016/j.neuron.2022.04.021

Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling.

Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3

The Journal of cell biology

2022 Jul 04

Ahmad, T;Vullhorst, D;Chaudhuri, R;Guardia, CM;Chaudhary, N;Karavanova, I;Bonifacino, JS;Buonanno, A;
PMID: 35579602 | DOI: 10.1083/jcb.202110167

Neuregulins (NRGs) are EGF-like ligands associated with cognitive disorders. Unprocessed proNRG3 is cleaved by BACE1 to generate the mature membrane-bound NRG3 ligand, but the subcellular site of proNRG3 cleavage, mechanisms underlying its transport into axons, and presynaptic accumulation remain unknown. Using an optogenetic proNRG3 cleavage reporter (LA143-NRG3), we investigate the spatial-temporal dynamics of NRG3 processing and sorting in neurons. In dark conditions, unprocessed LA143-NRG3 is retained in the trans-Golgi network but, upon photoactivation, is cleaved by BACE1 and released from the TGN. Mature NRG3 then emerges on the somatodendritic plasma membrane from where it is re-endocytosed and anterogradely transported on Rab4+ vesicles into axons via transcytosis. By contrast, the BACE1 substrate APP is sorted into axons on Rab11+ vesicles. Lastly, by a mechanism we denote "trans-synaptic retention," NRG3 accumulates at presynaptic terminals by stable interaction with its receptor ErbB4 on postsynaptic GABAergic interneurons. We propose that trans-synaptic retention may account for polarized expression of other neuronal transmembrane ligands and receptors.This is a work of the U.S. Government and is not subject to

Odorant Receptor Choice Mechanism Revealed by Analysis of a Highly Represented Odorant Receptor Transgene

SSRN Electronic Journal

2022 May 28

Makhlouf, M;D'Hulst, C;Omura, M;Rosa, A;Mina, R;Bernal-Garcia, S;Lempert, E;Saraiva, L;Feinstein, P;
| DOI: 10.2139/ssrn.4119003

In the mouse, more than 1,100 odorant receptors (ORs) are expressed in a monogenic and monoallelic fashion, referred to as singular gene expression. Using a 21bp singular-choice enhancer (x21), we radically increase representation of olfactory sensory neurons (OSNs) choosing a 5x21 enhanced OR transgene, but not overexpression of its mRNA on a per cell basis. RNA-sequencing and differential expression analysis identified 425 differentially expressed genes (DEGs). ORs make up 86% of all DEGs, of which 325 have decreased representation and 40 have increased representation. Underrepresented ORs include Class I, Class II and TAAR genes and within each of their respective olfactory bulb domains: DI, DII, and DIII (TAAR) we committedly observe multiple homogeneous glomeruli with an OR1A1-identity. The underrepresentation of endogenous, class-specific ORs across evolutionarily distinct cell types in favor of the expression of the 5x21-OR1A1 transgene argues that a common mechanism of singular gene choice is present for all OR-expressing OSNs.

Clinical and translational values of spatial transcriptomics

Signal transduction and targeted therapy

2022 Apr 01

Zhang, L;Chen, D;Song, D;Liu, X;Zhang, Y;Xu, X;Wang, X;
PMID: 35365599 | DOI: 10.1038/s41392-022-00960-w

The combination of spatial transcriptomics (ST) and single cell RNA sequencing (scRNA-seq) acts as a pivotal component to bridge the pathological phenomes of human tissues with molecular alterations, defining in situ intercellular molecular communications and knowledge on spatiotemporal molecular medicine. The present article overviews the development of ST and aims to evaluate clinical and translational values for understanding molecular pathogenesis and uncovering disease-specific biomarkers. We compare the advantages and disadvantages of sequencing- and imaging-based technologies and highlight opportunities and challenges of ST. We also describe the bioinformatics tools necessary on dissecting spatial patterns of gene expression and cellular interactions and the potential applications of ST in human diseases for clinical practice as one of important issues in clinical and translational medicine, including neurology, embryo development, oncology, and inflammation. Thus, clear clinical objectives, designs, optimizations of sampling procedure and protocol, repeatability of ST, as well as simplifications of analysis and interpretation are the key to translate ST from bench to clinic.

Molecular divergence of mammalian astrocyte progenitor cells at early gliogenesis

Development (Cambridge, England)

2022 Mar 01

Liu, J;Wu, X;Lu, Q;
PMID: 35253855 | DOI: 10.1242/dev.199985

During mammalian brain development, how different astrocytes are specified from progenitor cells is not well understood. In particular, whether astrocyte progenitor cells (APCs) start as a relatively homogenous population or whether there is early heterogeneity remains unclear. Here, we have dissected subpopulations of embryonic mouse forebrain progenitors using single-cell transcriptome analyses. Our sequencing data revealed two molecularly distinct APC subgroups at the start of gliogenesis from both dorsal and ventral forebrains. The two APC subgroups were marked, respectively, by specific expression of Sparc and Sparcl1, which are known to function in mature astrocytes with opposing activities for regulating synapse formation. Expression analyses showed that SPARC and SPARCL1 mark APC subgroups that display distinct temporal and spatial patterns, correlating with major waves of astrogliogenesis during development. Our results uncover an early molecular divergence of APCs in the mammalian brain and provide a useful transcriptome resource for the study of glial cell specification.

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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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