Mulderrig, L;Garaycoechea, JI;Tuong, ZK;Millington, CL;Dingler, FA;Ferdinand, JR;Gaul, L;Tadross, JA;Arends, MJ;O'Rahilly, S;Crossan, GP;Clatworthy, MR;Patel, KJ;
PMID: 34819667 | DOI: 10.1038/s41586-021-04133-7
Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1-4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5-7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5-/-) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5-/-Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.
Low, AYT;Goldstein, N;Gaunt, JR;Huang, KP;Zainolabidin, N;Yip, AKK;Carty, JRE;Choi, JY;Miller, AM;Ho, HST;Lenherr, C;Baltar, N;Azim, E;Sessions, OM;Ch'ng, TH;Bruce, AS;Martin, LE;Halko, MA;Brady, RO;Holsen, LM;Alhadeff, AL;Chen, AI;Betley, JN;
PMID: 34789878 | DOI: 10.1038/s41586-021-04143-5
The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.
Lam, BYH;Williamson, A;Finer, S;Day, FR;Tadross, JA;Gonçalves Soares, A;Wade, K;Sweeney, P;Bedenbaugh, MN;Porter, DT;Melvin, A;Ellacott, KLJ;Lippert, RN;Buller, S;Rosmaninho-Salgado, J;Dowsett, GKC;Ridley, KE;Xu, Z;Cimino, I;Rimmington, D;Rainbow, K;Duckett, K;Holmqvist, S;Khan, A;Dai, X;Bochukova, EG;Genes & Health Research Team, ;Trembath, RC;Martin, HC;Coll, AP;Rowitch, DH;Wareham, NJ;van Heel, DA;Timpson, N;Simerly, RB;Ong, KK;Cone, RD;Langenberg, C;Perry, JRB;Yeo, GS;O'Rahilly, S;
PMID: 34732894 | DOI: 10.1038/s41586-021-04088-9
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Mishra, A;Yao, LJ;Wasser, M;Khyriem, C;Malleret, B;McGovern, N;Albani, S;Chan, JKY;Ginhoux, F;
PMID: 34822780 | DOI: 10.1016/j.cell.2021.10.028
Wendisch, D;Dietrich, O;Mari, T;von Stillfried, S;Ibarra, I;Mittermaier, M;Mache, C;Chua, R;Knoll, R;Timm, S;Brumhard, S;Krammer, T;Zauber, H;Hiller, A;Pascual-Reguant, A;Mothes, R;Bülow, R;Schulze, J;Leipold, A;Djudjaj, S;Erhard, F;Geffers, R;Pott, F;Kazmierski, J;Radke, J;Pergantis, P;Baßler, K;Conrad, C;Aschenbrenner, A;Sawitzki, B;Landthaler, M;Wyler, E;Horst, D;Hippenstiel, S;Hocke, A;Heppner, F;Uhrig, A;Garcia, C;Machleidt, F;Herold, S;Elezkurtaj, S;Thibeault, C;Witzenrath, M;Cochain, C;Suttorp, N;Drosten, C;Goffinet, C;Kurth, F;Schultze, J;Radbruch, H;Ochs, M;Eils, R;Müller-Redetzky, H;Hauser, A;Luecken, M;Theis, F;Conrad, C;Wolff, T;Boor, P;Selbach, M;Saliba, A;Sander, L;
| DOI: 10.1016/j.cell.2021.11.033
COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.
van der Have, O;Mead, T;Westoo, C;Peruzzi, N;
| DOI: 10.1161/circ.144.suppl_1.13141
Introduction: Pulmonary arterial hypertension (PAH) is a lethal condition lacking curative pharmacotherapy. Expansion of the extracellular matrix occurs in early stages of pulmonary angiopathy, but the presence of individual matrix components warrants further investigation. Accumulation of the osmotically active matrix proteoglycan aggrecan has been associated with swelling and disruption of vessel wall integrity in systemic arteries. Whether aggrecan is present to any significant extent in PAH tissue, and what potential role it may have, is not known. Methods: Paraffin-embedded lung tissue from 11 patients with idiopathic PAH was imaged using synchrotron-based phase contrast micro-CT at the TOMCAT beamline, Swiss Light Source. Image analysis was performed in Fiji and Amira. Imaged blocks were subsequently sectioned for histology, immunohistochemistry with an aggrecan core protein antibody and RNAscope in situ hybridization. qPCR was performed to investigate gene expression. Failed donor lungs were used as controls. Results: Aggrecan core protein was identified in vascular lesions of all 11 patients with idiopathic PAH, localized to cellular rather than fibrotic or collagenous lesions. RNAscope in situ hybridization confirmed local production of ACAN mRNA in diseased vessels. Quantification of repeated immunohistochemistry demonstrated significantly increased accumulation of aggrecan in patients with idiopathic PAH compared to failed donor lung controls. ACAN and ADAMTS15 mRNA were also found to be up-regulated in pulmonary arteries from patients with IPAH, indicating ongoing proteolytic turnover. Image analysis and three-dimensional renderings of pulmonary arteries identified aggrecan in lumen-reducing lesions containing cellular connective tissue, at sites of intrapulmonary bronchopulmonary shunting and at sites of elevated pulmonary blood pressure. Conclusions: Our findings indicate local production and accumulation of aggrecan in pressure-related lesions of idiopathic PAH. This work strengthens the hypothesis that aggrecan plays a role in arterial adaptations to altered hemodynamics and is the first to suggest a role for aggrecan in pulmonary arterial homeostasis and idiopathic PAH.
Wang, L;Wang, B;Gasek, NS;Zhou, Y;Cohn, RL;Martin, DE;Zuo, W;Flynn, WF;Guo, C;Jellison, ER;Kim, T;Prata, LGPL;Palmer, AK;Li, M;Inman, CL;Barber, LS;Al-Naggar, IMA;Zhou, Y;Kuchel, GA;Meves, A;Tchkonia, T;Kirkland, JL;Robson, P;Xu, M;
PMID: 34813734 | DOI: 10.1016/j.cmet.2021.11.002
Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.
Pellegrino, G;Martin, M;Allet, C;Lhomme, T;Geller, S;Franssen, D;Mansuy, V;Manfredi-Lozano, M;Coutteau-Robles, A;Delli, V;Rasika, S;Mazur, D;Loyens, A;Tena-Sempere, M;Siepmann, J;Pralong, FP;Ciofi, P;Corfas, G;Parent, AS;Ojeda, SR;Sharif, A;Prevot, V;
PMID: 34795451 | DOI: 10.1038/s41593-021-00960-z
Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D2 receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that 'escort' them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A. Inhibition of DP1 signaling in the infantile preoptic region, where GnRH cell bodies reside, disrupts the correct wiring and firing of GnRH neurons, alters minipuberty or the first activation of the hypothalamic-pituitary-gonadal axis during infancy, and delays the timely acquisition of reproductive capacity. These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation.
Herz, J;Fu, Z;Kim, K;Dykstra, T;Wall, M;Li, H;Salvador, AF;Zou, B;Yan, N;Blackburn, SM;Andrews, PH;Goldman, DH;Papadopoulos, Z;Smirnov, I;Xie, XS;Kipnis, J;
PMID: 34793707 | DOI: 10.1016/j.neuron.2021.10.022
Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons. Exploration of snRNA-seq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways regulated by immune cells. IL-4Rα knockout in inhibitory (but not in excitatory) neurons was sufficient to impair contextual fear memory, and snRNA-seq from these mice pointed to IL-4-driven regulation of synaptic function in promoting memory. These findings provide new insights into complex neuroimmune interactions at the transcriptional and functional levels in neurons under physiological conditions.
Zhao, J;Lu, P;Wan, C;Huang, Y;Cui, M;Yang, X;Hu, Y;Zheng, Y;Dong, J;Wang, M;Zhang, S;Liu, Z;Bian, S;Wang, X;Wang, R;Ren, S;Wang, D;Yao, Z;Chang, G;Tang, F;Zhao, XY;
PMID: 34824237 | DOI: 10.1038/s41467-021-27172-0
Mammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells' identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.
Mahadevia, D;Saha, R;Manganaro, A;Chuhma, N;Ziolkowski-Blake, A;Morgan, AA;Dumitriu, D;Rayport, S;Ansorge, MS;
PMID: 34815379 | DOI: 10.1038/s41467-021-27092-z
Septal-hypothalamic neuronal activity centrally mediates aggressive behavior and dopamine system hyperactivity is associated with elevated aggression. However, the causal role of dopamine in aggression and its target circuit mechanisms are largely unknown. To address this knowledge gap, we studied the modulatory role of the population- and projection-specific dopamine function in a murine model of aggressive behavior. We find that terminal activity of ventral tegmental area (VTA) dopaminergic neurons selectively projecting to the lateral septum (LS) is sufficient for promoting aggression and necessary for establishing baseline aggression. Within the LS, dopamine acts on D2-receptors to inhibit GABAergic neurons, and septal D2-signaling is necessary for VTA dopaminergic activity to promote aggression. Collectively, our data reveal a powerful modulatory influence of dopaminergic synaptic input on LS function and aggression, effectively linking the clinically pertinent hyper-dopaminergic model of aggression with the classic septal-hypothalamic aggression axis.
Martín-Alonso, M;Iqbal, S;Vornewald, PM;Lindholm, HT;Damen, MJ;Martínez, F;Hoel, S;Díez-Sánchez, A;Altelaar, M;Katajisto, P;Arroyo, AG;Oudhoff, MJ;
PMID: 34795242 | DOI: 10.1038/s41467-021-26904-6
Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.
