Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA352463 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4919530.fastq.gz | Fastqsanger.gz | |||
| SRR4919540.fastq.gz | Fastqsanger.gz | |||
| SRR4919550.fastq.gz | Fastqsanger.gz | |||
| SRR4919560.fastq.gz | Fastqsanger.gz | |||
| SRR4919580.fastq.gz | Fastqsanger.gz |
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Project description:We developed a technique for generating hypothalamic neurons from human pluripotent stem cells. Here, as proof-of-principle, we examine the use of these cells in modeling of a monogenic form of severe obesity: PCSK1 deficiency. We generated PCSK1 (PC1/3)-deficient human embryonic stem cell (hESC) lines using both shRNA and CRISPR-Cas9, and investigated pro-opiomelanocortin (POMC) processing using hESC-differentiated hypothalamic neurons.
2017-01-31 | GSE89503 | GEO
Project description:Hypothalamic neuronal populations are central regulators of energy homeostasis and reproductive function. However, the ontogeny of these critical hypothalamic neuronal populations is largely unknown. Here, we reveal novel cellular fates of the hypothalamic Pomc-expressing precursors by combining mouse genetics with a conditional viral ribosome-tagging approach to phenotype neurons. Our results show that the Pomc-expressing precursors differentiate into discrete neuronal subpopulations that mediate not only energy balance (POMC and AgRP) but also reproductive physiology (Kisspeptin). Punches containing the mediobasal hypothalamus of Pomc-Cre:RiboTag mice and Pomc-Cre mice injected with the RiboTag viral vector (AAV-DIO-RiboTag) were homogenized and incubated with anti-hemagglutin (HA) antibodies and protein A/G magnetic beads to isolate the polysome-associated mRNAS in the Pomc-derived lineage and in adult POMC neurons, respectively. To identify differentially expressed transcripts, RNA from the immunoprecipitates was extracted, amplified, labelled and hybridized to MouseRef-8 v2 expression beadchips.
2015-04-16 | E-GEOD-56917 | biostudies-arrayexpress
Project description:Alterations in endoplasmic reticulum (ER) homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (a-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic a-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective a-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress, and establish a-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Total RNA was extracted from whole-liver of 6-week old control (3 biological replicates) and POMCMfn2KO mice (5 biological replicates)
2015-06-18 | E-GEOD-62263 | biostudies-arrayexpress
Project description:The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of 'Ghost' neurons endowed with atypical molecular and functional identity. Compared to 'classical' Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are ‘invisible’ to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers increase in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus, highlighting the ability of specialized neurons to adapt their funcitonal identity to adult-onset obesogenic stimuli
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Project description:Hypothalamic neuronal populations are central regulators of energy homeostasis and reproductive function. However, the ontogeny of these critical hypothalamic neuronal populations is largely unknown. Here, we reveal novel cellular fates of the hypothalamic Pomc-expressing precursors by combining mouse genetics with a conditional viral ribosome-tagging approach to phenotype neurons. Our results show that the Pomc-expressing precursors differentiate into discrete neuronal subpopulations that mediate not only energy balance (POMC and AgRP) but also reproductive physiology (Kisspeptin).
2015-04-16 | GSE56917 | GEO
Project description:Alterations in endoplasmic reticulum (ER) homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (a-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic a-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective a-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress, and establish a-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D.
2015-06-18 | GSE62263 | GEO
Project description:Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive.We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons in E15.5 mice embryos. Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons.Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but absent in NPY/AgRP neurons. To study the role of Prdm12 in vivo, we developed and characterized a floxed Prdm12 allele. Selective ablation of Prdm12 in embryonic POMC neurons led to significantly reduced Pomc expression as well as early-onset obesity in mice of either sex that recapitulates symptoms of human POMC deficiency. Interestingly, however, specific deletion of Prdm12 in adult POMC neurons showed that it is no longer required for Pomc expression nor energy balance. Collectively, these findings establish a critical role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis. Finally, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the hypothalamus whose neurodevelopment remains poorly studied.
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Project description:Mitofusin 1 (Mfn1) is a transmembrane GTPase protein implicated in mitochondrial fusion. To investigate the potential role of Mfn1 in energy balance and metabolism control we generated mice lacking Mfn1 specifically in hypothalamic POMC neurons (POMCMfn1KO). We used microarrays to determine gene expression changes resulting from deletion of Mfn1 in POMC neurons under fed and fasting conditions
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Project description:Over recent decades, research has established the hypothalamus, particularly the arcuate nucleus, as a central hub for the homeostatic control of energy balance. The hypothalamic arcuate nucleus is a pivotal regulator of energy balance, containing anorexic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons, which exert opposing effects on energy homeostasis. However, the molecular identity of “non-AgRP, non-POMC” neurons remains unclear. We identified a distinct neuronal subtype characterized by the absence of Agrp and Pomc expressions, while exhibiting robust Crabp1 expression.
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Project description:The activity of the endoribonuclease Dicer is crucial to produce the mature form of most microRNAs (miRNAs). Recent studies indicate that lack of miRNAs in different neuronal types results in a range of anatomical and behavioural phenotypes. In the present study we aimed to investigate the developmental and metabolic consequences of miRNA ablation in hypothalamic POMC neurons studying mice with a conditional deletion of Dicer in this population of neurons (POMCDicerKO). These mice exhibited a progressive obese phenotype characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism and alterations in the pituitary-adrenal axis. The development of the obese phenotype was paralleled by a POMC neuron degenerative process that was complete by 6 weeks of age. Furthermore, immunohistochemistry and gene expression studies in control C57Bl/6 adult mice showed that Dicer was expressed in relevant hypothalamic areas and neurons implicated in energy balance, and that its expression was regulated by nutrient availability. Collectively, our results highlight a crucial role for miRNAs in POMC neuron survival and the consequent development of neurodegenerative obesity. Total RNA was extracted from hypothalamic microdissections of 2-week old control and POMCDicerKO mice using the RNeasy micro spin columns (Qiagen, Venlo, The Netherlands). Ten micrograms of total RNA were converted into cRNA, biotinylated, fragmented, and hybridized to GeneChip Mouse Genome 430 2.0 (Affymetrix, Santa Clara, CA). Six microarrays were hybridized with three independent samples from control and POMCDicerKO mice.
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