Recent CIG publications Archive

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PLoS Genet.: auth.: group Fankhauser

PLoS Genet. 2022 May 27;18(5):e1010213. doi: 10.1371/journal.pgen.1010213. eCollection 2022 May.

Shade suppresses wound-induced leaf repositioning through a mechanism involving PHYTOCHROME KINASE SUBSTRATE (PKS) genes

Anne-Sophie Fiorucci 1Olivier Michaud 1Emanuel Schmid-Siegert 2Martine Trevisan 1Laure Allenbach Petrolati 1Yetkin Çaka Ince 1Christian Fankhauser 1

Abstract

Shaded plants challenged with herbivores or pathogens prioritize growth over defense. However, most experiments have focused on the effect of shading light cues on defense responses. To investigate the potential interaction between shade-avoidance and wounding-induced Jasmonate (JA)-mediated signaling on leaf growth and movement, we used repetitive mechanical wounding of leaf blades to mimic herbivore attacks. Phenotyping experiments with combined treatments on Arabidopsis thaliana rosettes revealed that shade strongly inhibits the wound effect on leaf elevation. By contrast, petiole length is reduced by wounding both in the sun and in the shade. Thus, the relationship between the shade and wounding/JA pathways varies depending on the physiological response, implying that leaf growth and movement can be uncoupled. Using RNA-sequencing, we identified genes with expression patterns matching the hyponastic response (opposite regulation by both stimuli, interaction between treatments with shade dominating the wound signal). Among them were genes from the PKS (Phytochrome Kinase Substrate) family, which was previously studied for its role in phototropism and leaf positioning. Interestingly, we observed reduced shade suppression of the wounding effect in pks2pks4 double mutants while a PKS4 overexpressing line showed constitutively elevated leaves and was less sensitive to wounding. Our results indicate a trait-specific interrelationship between shade and wounding cues on Arabidopsis leaf growth and positioning. Moreover, we identify PKS genes as integrators of external cues in the control of leaf hyponasty further emphasizing the role of these genes in aerial organ positioning.

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NPJ Genom Med.: auth.: group Reymond and co-auth.: group Vastenhouw

NPJ Genom Med. 2022 Jun 17;7(1):38. doi: 10.1038/s41525-022-00308-x.

Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts

Giuliana Giannuzzi 1 2Nicolas Chatron 3 4 5Katrin Mannik 3 6Chiara Auwerx 3 7 8 9Sylvain Pradervand 3Gilles Willemin 3Kendra Hoekzema 10Xander Nuttle 11 12 13Jacqueline Chrast 3Marie C Sadler 7 8 9Eleonora Porcu 3 8 916p11.2 ConsortiumYann Herault 14Bertrand Isidor 15Brigitte Gilbert-Dussardier 16Evan E Eichler 10 17Zoltan Kutalik 7 8 9Alexandre Reymond 3

Abstract

Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3-8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.

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J Chem Neuroanat.: auth.: S.Croizier

J Chem Neuroanat. 2022 Jun 6;123:102117. doi: 10.1016/j.jchemneu.2022.102117. 

Molecular control of the development of hypothalamic neurons involved in metabolic regulation

Sophie Croizier 1Sebastien G Bouret 2

Abstract

The hypothalamus is a large brain region made of nuclei and areas involved in the control of behaviors and physiological regulations. Among them, the arcuate nucleus (ARH) and the lateral hypothalamic area (LHA) contain key neuronal populations expressing the pro-opiomelanocortin (POMC), the agouti-related peptide (AgRP), and the melanin-concentrating hormone (MCH), respectively, that are involved in goal-oriented behaviors (such as feeding behavior) and glucose homeostasis. These neuronal populations are generated from distinct parts of the germinative neuroepithelium during embryonic life, and acquire their cell fate under the influence of morphogen proteins, specific transcription factors, and epigenetic modulators. POMC and MCH neuronal development continues by sending long descending axonal projections before birth under the control of axon guidance molecules such as Netrin1 and Slit2. Later, during the postnatal period, POMC and AgRP neurons develop intra-hypothalamic projections notably to the paraventricular nucleus of the hypothalamus through the influence of other axon guidance cues such as the class3 Semaphorins. Other cellular processes, such as autophagy and primary cilia function, and hormonal cues also appear critical for the proper development of POMC neurons.

Keywords: Development; Hypothalamus; Melanin-concentrating hormone; Melanocortin; Neuropeptide Y; Pro-opiomelanocortin.

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Diabetes Obes Metab.: co-auth.: B.Thorens

Diabetes Obes Metab. 2022 Jun 8. doi: 10.1111/dom.14794. Online ahead of print.

In vivo and in vitro characterisation of GL0034, a novel long-acting GLP-1 receptor agonist

Ben Jones 1Vinod Burade 2Elina Akalestou 3Yusman Manchanda 3Zenouska Ramchunder 3Gaëlle Carrat 3Marie-Sophie Nguyen-Tu 3Piero Marchetti 4Lorenzo Piemonti 5Isabelle Leclerc 3 6Thennati Rajamannar 2Tina Vilsboll 7Bernard Thorens 8Alejandra Tomas 3Guy A Rutter 3 9 6

Abstract

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for type 2 diabetes (T2D). Here, we describe the in vitro characteristics and anti-diabetic in vivo efficacy of the novel GLP-1RA GL0034.

Materials and methods: GLP-1R kinetic binding parameters, cAMP signalling, endocytosis and recycling were measured using HEK293 and INS-1 832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1 832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice.

Results: Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and β-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg).

Conclusions: GL0034 is a G protein-biased agonist that shows powerful anti-diabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with T2D. This article is protected by copyright. All rights reserved.

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Cell Res.: auth.: group Vastenhouw

Cell Res. 2022 May 30. doi: 10.1038/s41422-022-00670-6. Online ahead of print.

Maternally loaded RNAs: no time to die

Martino Ugolini 1Nadine L Vastenhouw 2

Upon fertilization, the animal genome is often inactive and development is driven by proteins and transcripts that are stored in the egg during oogenesis. In a recent Cell Research paper, Shi et al. show that the RNA helicase Ddx3xb facilitates the translation of stored transcripts in zebrafish embryos by a phase separation-dependent process.

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Front Immunol.: co-auth.: group Fajas & Lopez-Mejia

Front Immunol. 2022 May 16;13:882867. doi: 10.3389/fimmu.2022.882867. eCollection 2022.

Sex-Biased Control of Inflammation and Metabolism by a Mitochondrial Nod-Like Receptor

Tiia Snäkä 1Amel Bekkar 1Chantal Desponds 1Florence Prével 1Stéphanie Claudinot 1Nathalie Isorce 1Filipa Teixeira 1Coline Grasset 1Ioannis Xenarios 2 3Isabel C Lopez-Mejia 3Lluis Fajas 3Nicolas Fasel 1

Abstract

Mitochondria regulate steroid hormone synthesis, and in turn sex hormones regulate mitochondrial function for maintaining cellular homeostasis and controlling inflammation. This crosstalk can explain sex differences observed in several pathologies such as in metabolic or inflammatory disorders. Nod-like receptor X1 (NLRX1) is a mitochondria-associated innate receptor that could modulate metabolic functions and attenuates inflammatory responses. Here, we showed that in an infectious model with the human protozoan parasite, Leishmania guyanensis, NLRX1 attenuated inflammation in females but not in male mice. Analysis of infected female and male bone marrow derived macrophages showed both sex- and genotype-specific differences in both inflammatory and metabolic profiles with increased type I interferon production, mitochondrial respiration, and glycolytic rate in Nlrx1-deficient female BMDMs in comparison to wild-type cells, while no differences were observed between males. Transcriptomics of female and male BMDMs revealed an altered steroid hormone signaling in Nlrx1-deficient cells, and a “masculinization” of Nlrx1-deficient female BMDMs. Thus, our findings suggest that NLRX1 prevents uncontrolled inflammation and metabolism in females and therefore may contribute to the sex differences observed in infectious and inflammatory diseases.

Keywords: inflammation; innate immunity; metabolism; nod-like receptor X1; sex.