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Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand.
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Metabolismo Energético , Microbioma Gastrointestinal , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/fisiología , Homeostasis , Tejido Adiposo Blanco/metabolismo , Animales , Apoptosis , Frío , Enterocitos/citología , Enterocitos/metabolismo , Vida Libre de Gérmenes , Resistencia a la Insulina , Absorción Intestinal , Ratones , Verrucomicrobia/metabolismoRESUMEN
INTRODUCTION: We developed a multimarker blood test result interpretation tool for the clinical dementia practice, including phosphorylated (P-)tau181, amyloid-beta (Abeta)42/40, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). METHODS: We measured the plasma biomarkers with Simoa (n = 1199), applied LASSO regression for biomarker selection and receiver operating characteristics (ROC) analyses to determine diagnostic accuracy. We validated our findings in two independent cohorts and constructed a visualization approach. RESULTS: P-tau181, GFAP, and NfL were selected. This combination had area under the curve (AUC) = 83% to identify amyloid positivity in pre-dementia stages, AUC = 87%-89% to differentiate Alzheimer's or controls from frontotemporal dementia, AUC = 74%-76% to differentiate Alzheimer's or controls from dementia with Lewy bodies. Highly reproducible AUCs were obtained in independent cohorts. The resulting visualization tool includes UpSet plots to visualize the stand-alone biomarker results and density plots to visualize the biomarker results combined. DISCUSSION: Our multimarker blood test interpretation tool is ready for testing in real-world clinical dementia settings. HIGHLIGHTS: We developed a multimarker blood test interpretation tool for clinical dementia practice. Our interpretation tool includes plasma biomarkers P-tau, GFAP, and NfL. Our tool is particularly useful for Alzheimer's and frontotemporal dementia diagnosis.
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Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype-phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3ß, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.
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Síndrome de Down , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cognición , Modelos Animales de Enfermedad , Síndrome de Down/genética , Síndrome de Down/patología , Hipocampo/metabolismo , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: The key Alzheimer's disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aß42 and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers. METHODS: Participants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months. RESULTS: Overall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up to r=0.50 (p<0.001) among amyloid, r=0.43 (p=0.002) among tau, and r=-0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers. CONCLUSION: The implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Fragmentos de Péptidos/líquido cefalorraquídeo , Disfunción Cognitiva/diagnósticoRESUMEN
Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down's syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes.
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Síndrome de Down/genética , Regulación de la Expresión Génica/genética , Genoma/genética , Transcriptoma/genética , Animales , Células Cultivadas , Cromatina/química , Cromatina/metabolismo , Cromosomas Humanos Par 21/genética , Cromosomas de los Mamíferos/genética , Momento de Replicación del ADN , Síndrome de Down/patología , Femenino , Feto/citología , Fibroblastos , Histonas/química , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Lisina/metabolismo , Masculino , Metilación , Ratones , Gemelos Monocigóticos/genéticaRESUMEN
Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.
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Anomalías Múltiples/genética , Duplicación Cromosómica/genética , Cognición , Discapacidad Intelectual/genética , Proteínas Nucleares/genética , Animales , Peso Corporal , Encéfalo/metabolismo , Encéfalo/ultraestructura , Deleción Cromosómica , Estructuras Cromosómicas/genética , Estructuras Cromosómicas/metabolismo , Cromosomas Humanos Par 17/genética , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Eliminación de Gen , Reordenamiento Génico , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasticidad Neuronal/genética , Proteínas Nucleares/metabolismo , Transmisión Sináptica/genética , Regulación hacia ArribaRESUMEN
The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
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Autofagia/fisiología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Repeticiones WD40/fisiología , Animales , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Microtúbulos/metabolismo , Microtúbulos/fisiología , Neurogénesis/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Fenotipo , Células Madre/metabolismo , Células Madre/fisiologíaRESUMEN
The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.
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Deleción Cromosómica , Duplicación Cromosómica/genética , Cognición , Adiposidad , Alelos , Animales , Arilsulfotransferasa/genética , Arilsulfotransferasa/metabolismo , Conducta Animal , Peso Corporal , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cromosomas de los Mamíferos/genética , Anomalías Craneofaciales/genética , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Reordenamiento Génico/genética , Hipocampo/fisiopatología , Memoria , Ratones Endogámicos C57BL , Actividad Motora , Fenotipo , Transmisión Sináptica/genética , Síndrome , DesteteRESUMEN
Background: Autism spectrum disorders affect more than 1% of the population, impairing social communication and increasing stereotyped behaviours. A micro-deletion of the 16p11.2 BP4-BP5 chromosomic region has been identified in 1% of patients also displaying intellectual disabilities. In mouse models generated to understand the mechanisms of this deletion, learning and memory deficits were pervasive in most genetic backgrounds, while social communication deficits were only detected in some models. Methods: To complement previous studies, we itemized the social deficits in the mouse model of 16p11.2 deletion on a hybrid C57BL/6N × C3H.Pde6b+ genetic background. We examined whether behavioural deficits were visible over long-term observation periods lasting several days and nights, to parallel everyday-life assessment of patients. We recorded the individual and social behaviours of mice carrying a heterozygous deletion of the homologous 16p11.2 chromosomic region (hereafter Del/+) and their wild-type littermates from both sexes over two or three consecutive nights during social interactions of familiar mixed-genotype quartets of males and of females, and of same-genotype unfamiliar female pairs. Results: We observed that Del/+ mice of both sexes increased significantly their locomotor activity compared to wild-type littermates. In the social domain, Del/+ mice of both sexes displayed widespread deficits, even more so in males than in females in quartets of familiar individuals. In pairs, significant perturbations of the organisation of the social communication and behaviours appeared in Del/+ females. Discussion: Altogether, this suggests that, over long recording periods, the phenotype of the 16p11.2 Del/+ mice was differently affected in the locomotor activity and the social domains and between the two sexes. These findings confirm the importance of testing models in long-term conditions to provide a comprehensive view of their phenotype that will refine the study of cellular and molecular mechanisms and complement pre-clinical targeted therapeutic trials.
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Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear. Here, we provide a systematic characterization of the effects in a comparative multi-tissue RNA sequencing approach following exposure of mice to 10 °C, 22 °C, or 34 °C in a panel of organs consisting of spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, quadriceps, subcutaneous-, visceral- and brown adipose tissues. We highlight that transcriptional responses to temperature alterations exhibit a high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, and show that the tissue-specificity is not directed by the distinct basic gene expression pattern exhibited by the various organs. Our study places the adaptation of individual tissues to different temperatures in a whole-organism framework and provides integrative transcriptional analysis necessary for understanding the temperature-mediated biological programming.
Humans, mice and most other mammals are constantly exposed to fluctuations in the temperature of their environment. These fluctuations cause striking metabolic effects in the body, for example, exposure to cold promotes burning of calories to generate heat, thereby reducing how much fat accumulates in the body. On the other hand, warmer temperatures strengthen the bones and protect against a bone disease known as osteoporosis. As such, it has been suggested that exposure to alternating warm or cold temperatures could be a potential lifestyle intervention that conveys various benefits to our health. Our body stores fat in tissues known as adipose tissues, which are found all over the body including under the skin and around our major organs and muscles. Exposure to cold triggers changes in the activities of some genes in the adipose tissues to burn more calories. But it remains unclear how temperature affects the activities of other organs with respect to their expression of genes in the whole-body context. Hadadi, Spiljar et al. used an RNA sequencing approach to study the activities of genes in various tissues of mice exposed to cold (10°C), room temperature (22°C), or mild warm (34°C). The experiments revealed numerous genes whose levels were different in the various organs and temperatures tested. Overall, adipose tissues experienced the biggest changes in gene levels between different temperatures, followed by tissues involved in immune responses, and the brain and spinal cord tissues. Each organ changed gene expression levels in its own way. , and this was not due to the different intimate gene expression profile between the various organs. These findings improve our understanding of how changes in temperature affect mammals by putting the responses of individual tissues into the context of the whole body. Hadadi, Spiljar et al. also generated a web-based, free-to-use application to allow others to view and further analyze the data collected in this work for gene levels in the various organs of interest.
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Frío , Transcriptoma , Aclimatación/genética , Tejido Adiposo Pardo/metabolismo , Animales , Ratones , TermogénesisRESUMEN
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). The understanding of genotype-phenotype relationships, the identification of driver genes and various proofs of concept for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16, homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 from Pisd-ps2/Scaf8 to Pde10a, containing 46 genes not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CRISPR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures were changed, suggesting genetic interactions between the Mir155-Zbtb21 and Scaf8-Pde10a intervals. Thus, Ts66Yah mice have stronger construct and face validity than Ts65Dn mice for mimicking consequences of DS genetic overdosage. Furthermore, this study is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21. This article has an associated First Person interview with the first author of the paper.
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Síndrome de Down , Humanos , Ratones , Animales , Síndrome de Down/genética , Hidrolasas Diéster FosfóricasRESUMEN
Down syndrome (DS) is the most frequent genetic disorder leading to intellectual disabilities and is caused by three copies of human chromosome 21. Mouse models are widely used to better understand the physiopathology in DS or to test new therapeutic approaches. The older and the most widely used mouse models are the trisomic Ts65Dn and the Ts1Cje mice. They display deficits similar to those observed in DS people, such as those in behavior and cognition or in neuronal abnormalities. The Ts65Dn model is currently used for further therapeutic assessment of candidate drugs. In both models, the trisomy was induced by reciprocal chromosomal translocations that were not further characterized. Using a comparative genomic approach, we have been able to locate precisely the translocation breakpoint in these two models and we took advantage of this finding to derive a new and more efficient Ts65Dn genotyping strategy. Furthermore, we found that the translocations introduce additional aneuploidy in both models, with a monosomy of seven genes in the most telomeric part of mouse chromosome 12 in the Ts1Cje and a trisomy of 60 centromeric genes on mouse chromosome 17 in the Ts65Dn. Finally, we report here the overexpression of the newly found aneuploid genes in the Ts65Dn heart and we discuss their potential impact on the validity of the DS model.
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Modelos Animales de Enfermedad , Síndrome de Down/genética , Translocación Genética , Trisomía , Animales , Línea Celular , Hibridación Genómica Comparativa , Roturas del ADN , Síndrome de Down/metabolismo , Síndrome de Down/patología , Duplicación de Gen , Genotipo , Ratones , Ratones Endogámicos BALB C , Mutación , Miocardio/metabolismo , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Mesenchymal-derived osteoblasts play a key role in bone formation via synthesis and mineralization of the bone and bone remodeling. Osteoclasts are multinucleated cells of hematopoietic origin with a role in bone resorption. Here, we describe a protocol for generating primary cultures of these two cell types from bone tissue including the femur, tibia, and humerus of young mice. We describe methods for addressing their activity and/or differentiation, enabling studying the effects of various treatments during or following differentiation ex vivo. For further practical example of using these protocols, please refer to Chevalier et al. (2020).
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Osteoblastos/citología , Osteoblastos/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Cultivo Primario de Células , Animales , RatonesRESUMEN
BACKGROUND: Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway. METHODS: Here, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. RESULTS: We found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway. LIMITATIONS: The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background. CONCLUSION: These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.
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Trastorno Autístico/etiología , Trastorno Autístico/metabolismo , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/metabolismo , Discapacidad Intelectual/etiología , Discapacidad Intelectual/metabolismo , Aprendizaje , Memoria , Transducción de Señal/efectos de los fármacos , Complejos de Ubiquitina-Proteína Ligasa/deficiencia , Proteína de Unión al GTP rhoA/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Alelos , Animales , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 16/metabolismo , Cognición , Modelos Animales de Enfermedad , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Ratones , Ratones Noqueados , Fenotipo , Resultado del Tratamiento , Quinasas Asociadas a rho/metabolismoRESUMEN
Autoimmunity is energetically costly, but the impact of a metabolically active state on immunity and immune-mediated diseases is unclear. Ly6Chi monocytes are key effectors in CNS autoimmunity with an elusive role in priming naive autoreactive T cells. Here, we provide unbiased analysis of the immune changes in various compartments during cold exposure and show that this energetically costly stimulus markedly ameliorates active experimental autoimmune encephalomyelitis (EAE). Cold exposure decreases MHCII on monocytes at steady state and in various inflammatory mouse models and suppresses T cell priming and pathogenicity through the modulation of monocytes. Genetic or antibody-mediated monocyte depletion or adoptive transfer of Th1- or Th17-polarized cells for EAE abolishes the cold-induced effects on T cells or EAE, respectively. These findings provide a mechanistic link between environmental temperature and neuroinflammation and suggest competition between cold-induced metabolic adaptations and autoimmunity as energetic trade-off beneficial for the immune-mediated diseases.
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Encefalomielitis Autoinmune Experimental , Enfermedades Neuroinflamatorias , Traslado Adoptivo , Animales , Autoinmunidad , Ratones , Ratones Endogámicos C57BL , Células Th17RESUMEN
Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation. Combinatorial metagenomics/metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.
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Microbioma Gastrointestinal , Osteoporosis/prevención & control , Animales , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoporosis/metabolismo , OvariectomíaRESUMEN
Down syndrome is a common genetic disorder caused by trisomy of chromosome 21. Brain development in affected foetuses might be improved through prenatal treatment. One potential target is DYRK1A, a multifunctional kinase encoded by chromosome 21 that, when overexpressed, alters neuronal excitation-inhibition balance and increases GAD67 interneuron density. We used a green tea extract enriched in EGCG to inhibit DYRK1A function only during gestation of transgenic mice overexpressing Dyrk1a (mBACtgDyrk1a). Adult mice treated prenatally displayed reduced levels of inhibitory markers, restored VGAT1/VGLUT1 balance, and rescued density of GAD67 interneurons. Similar results for gabaergic and glutamatergic markers and interneuron density were obtained in Dp(16)1Yey mice, trisomic for 140 chromosome 21 orthologs; thus, prenatal EGCG exhibits efficacy in a more complex DS model. Finally, cognitive and behaviour testing showed that adult Dp(16)1Yey mice treated prenatally had improved novel object recognition memory but do not show improvement with Y maze paradigm. These findings provide empirical support for a prenatal intervention that targets specific neural circuitries.
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Catequina/análogos & derivados , Síndrome de Down/dietoterapia , Glutamato Descarboxilasa/fisiología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Té , Animales , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Catequina/administración & dosificación , Cognición , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Síndrome de Down/psicología , Femenino , Interneuronas/patología , Intercambio Materno-Fetal , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Embarazo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Quinasas DyrKRESUMEN
A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.
Asunto(s)
Trastorno Autístico/genética , Trastornos de los Cromosomas/genética , Anomalías Craneofaciales/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidad Intelectual/genética , Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Femenino , Humanos , MasculinoRESUMEN
Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals. Genetic and pharmacological suppression of the LPS-TLR4 pathway or transplantation with Tlr4-/- bone-marrow-derived hematopoietic cells increases beige fat development and ameliorates diet-induced fatty liver, while Tlr4-/- or microbiota-depleted mice are resistant to further CR-stimulated metabolic alterations. These data reveal signals critical for our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.