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Ectopic misexpression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to hyperphagia and neurodevelopmental defects in Sim1 haploinsufficiency

ABSTRACT: Single cell sequencing of Sim1-Cre;tdTomato+ FACS sorted cells from hypothalami of wildtype and Sim1 heterozygous mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE166616 | GEO | 2021/09/17

REPOSITORIES: GEO

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Ectopic expression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to defects in Sim1 haploinsufficiency

Project description:Description Irx3 and Irx5 misexpression in paraventricular nucleus of the hypothalamus leads to hyperphagic obesity in Sim1 haploinsufficiency. The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing neurons critical for feeding regulation. Sim1 haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of Sim1 haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of Sim1+ PVH neurons, which are differentially affected by Sim1 haploinsufficiency. The Iroquois homeobox genes Irx3 and Irx5 have been implicated in the hypothalamic control of energy homeostasis. We found that Irx3 and Irx5 are ectopically expressed in the Sim1+ PVH cells of Sim1+/− mice. By reducing their dosage and PVH-specific deletion of Irx3, we demonstrate that misexpression of Irx3 and Irx5 contributes to the defects of Sim1+/− mice. Our results illustrate abnormal hypothalamic activities of Irx3 and Irx5 as a central mechanism disrupting PVH development and feeding regulation in Sim1 haploinsufficiency.

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Ectopic misexpression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to hyperphagia and neurodevelopmental defects in Sim1 haploinsufficiency

Project description:Ectopic misexpression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to hyperphagia and neurodevelopmental defects in Sim1 haploinsufficiency

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Circular chromatin conformation capture (4C-seq) experiments for viewpoints on the promoters of Rpgrip1l/Fto, Irx3, Irx5 and Irx6 in mouse hypothalamus

Project description:We performed 4C to analyze long-range interactions between the promoters of Rpgrip1l/Fto, Irx3, Irx5 and Irx6 and a region in the first intron of the FTO gene that has been associated with obesity. 3 whole mouse hypothalami were used to obtain the data.

2021-03-20 | E-MTAB-10195 | biostudies-arrayexpress

Promoter or enhancer activation by CRISPRa rescues haploinsufficiency caused obesity

Project description:Haploinsufficiency, having only one functional copy of a gene, leads to a wide-range of human diseases. Using obesity as a disease model, we tested whether haploinsufficiency can be rescued by CRISPR-mediated activation (CRISPRa) of the normal allele. Haploinsufficiency of either SIM1 or MC4R, results in severe obesity in humans and mice. In transgenic mice, CRISPRa targeting of the Sim1 promoter or its ~270kb distant hypothalamic enhancer, rescued the obesity phenotype in Sim1 heterozygous mice. Interestingly, despite using a ubiquitous promoter for CRISPRa, Sim1 was upregulated only in tissues where the promoter or enhancer are active, suggesting that cis-regulatory elements can determine CRISPRa tissue-specificity. To evaluate the potential therapeutic use of CRISPRa, we injected CRISPRa-rAAV into the hypothalamus, leading to reversal of the obesity phenotype in Sim1 and Mc4r heterozygous mice. Our results show that CRISPRa can be developed as a gene regulation therapy (GRT) to treat altered gene dosage diseases.

2018-12-17 | GSE112250 | GEO

Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology.

Project description:The Iroquois homeobox (Irx) homeodomain transcription factors are important for several aspects of embryonic development. In the developing heart, individual Irx genes are important for certain postnatal cardiac functions, including cardiac repolarization (Irx5) and rapid ventricular conduction (Irx3). Irx genes are expressed in dynamic and partially overlapping patterns in the developing heart. Here we show in mice that Irx3 and Irx5 have redundant function in the endocardium to regulate atrioventricular canal morphogenesis and outflow tract formation. Our data suggest that direct transcriptional repression of Bmp10 by Irx3 and Irx5 in the endocardium is required for ventricular septation. A postnatal deletion of Irx3 and Irx5 in the myocardium leads to prolongation of atrioventricular conduction, due in part to activation of expression of the Na(+) channel protein Nav1.5. Surprisingly, combined postnatal loss of Irx3 and Irx5 results in a restoration of the repolarization gradient that is altered in Irx5 mutant hearts, suggesting that postnatal Irx3 activity can be repressed by Irx5. Our results have uncovered complex genetic interactions between Irx3 and Irx5 in embryonic cardiac development and postnatal physiology.

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Genome-wide analysis of gene expression in the paraventricular nucleus of Sim1-Cre specific DNMT3a deletion mice.

2014-09-01 | GSE42304 | GEO

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis.

Project description:Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3- /Irx5- mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3-/- cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β-catenin-signalling. In contrast, IRX5-/- cells displayed activation of Hippo and non-canonical WNT-signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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IRX3 and IRX5 collaborate during ovary development and follicle formation to establish responsive granulosa cells in the adult mouse†.

Project description:Healthy development of ovarian follicles depends on appropriate interactions and function between oocytes and their surrounding granulosa cells. Previously, we showed that double knockout of Irx3 and Irx5 (Irx3/5 DKO) in mice resulted in abnormal follicle morphology and follicle death. Further, female mouse models of individual Irx3 or Irx5 knockouts were both subfertile but with distinct defects. Notably, the expression profile of each gene suggests independent roles for each; first, they are colocalized in pre-granulosa cells during development that then progresses to include oocyte expression during germline nest breakdown and primordial follicle formation. Thereafter, their expression patterns diverge between oocytes and granulosa cells coinciding with the formulation and maturation of intimate oocyte-granulosa cell interactions. The objective of this study was to investigate the contributions of Irx5 and somatic cell-specific expression of Irx3 during ovarian development. Our results show that Irx3 and Irx5 contribute to female fertility through different mechanisms and that Irx3 expression in somatic cells is important for oocyte quality and survival. Based on evaluation of a series of genetically modified mouse models, we conclude that IRX3 and IRX5 collaborate in the same cells and then in neighboring cells to foster a healthy and responsive follicle. Long after these two factors have extinguished, their legacy enables these intercellular connections to mature and respond to extracellular signals to promote follicle maturation and ovulation.

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Genome-wide analysis of gene expression in the paraventricular nucleus of Sim1-Cre specific DNMT3a deletion mice.

Project description:Analysis of gene expression in the paraventricular nucleus in the hypothalamus (PVH) of WT and Sim1-Cre specific DNMT3a deletion mice. Results provide important information about genes regulated by DNMT3a. For the gene expression profiling, total RNA was extracted from PVH of WT and Sim1-Cre specific DNMT3a deletion mice (C57BL6 background) at 6 weeks old using Qiagen RNeasy Lipid Tissue Mini Kit (Qiagen) and Phase Lock Gel (5 Prime Inc., Gaitherburg, MD). To make sure reproducibility and biological significance, triple hybridizations were performed for each genotype with the RNA from 3 indipendent PVH samples, each sample contains RNA from 5 animals. Genomics and Microarray Core Facility at UTSW (http://microarray.swmed.edu/) checked RNA quality with Bioanalyzer Chip and processed the samples for hybridization with Illumina Mouse-6 V2 BeadChip (Illumina Inc., San Diego, CA). We used GeneSpring GX (Agilent Technologies, Santa Clara, CA) for data analysis.

2014-09-01 | E-GEOD-42304 | biostudies-arrayexpress

Irx3 and Irx5 regulate hypothalamic postnatal neurogenesis and leptin sensitivity

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-18 | GSE154981 | GEO