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Prox1 downregulation is a prerequisite for the maturation and expansion of postnatal murine beta cells

ABSTRACT: Alterations in the expression of key transcription factors can be harmful for pancreatic beta cell homeostasis and could lead to diabetes. This study uncovered that Prox1 overexpression obstructs beta cell maturation and results in severe hyperglycemia. The function of β-cells is key for glucose homeostasis because they supply insulin to the entire body. Genetic or metabolic conditions that disrupt the complex physiology of β-cells can lead to diabetes mellitus, a prevalent life-threatening disease. Here we investigated whether sustained Prox1 expression is incompatible with β-cell development using a transgenic mouse approach, and report that β-cell maturation is drastically impaired in the presence of high levels of Prox1.

ORGANISM(S): Mus musculus

PROVIDER: GSE68133 | GEO | 2016/02/11

SECONDARY ACCESSION(S): PRJNA281871

REPOSITORIES: GEO

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Prox1 downregulation is a prerequisite for the maturation and expansion of postnatal murine beta cells

Project description:Alterations in the expression of key transcription factors can be harmful for pancreatic beta cell homeostasis and could lead to diabetes. This study uncovered that Prox1 overexpression obstructs beta cell maturation and results in severe hyperglycemia. The function of Î²-cells is key for glucose homeostasis because they supply insulin to the entire body. Genetic or metabolic conditions that disrupt the complex physiology of Î²-cells can lead to diabetes mellitus, a prevalent life-threatening disease. Here we investigated whether sustained Prox1 expression is incompatible with Î²-cell development using a transgenic mouse approach, and report that Î²-cell maturation is drastically impaired in the presence of high levels of Prox1. We used microarrays to identify gene expression profiles and pathways that are differentially activated when Prox1 is overexpressed in murine pancreatic beta cells.

2016-02-11 | E-GEOD-68133 | biostudies-arrayexpress

Prox1 inhibits axon outgrowth during central nervous system development

Project description:During central nervous system (CNS) development, proper and timely induction of axon elongation is critical for generating functional, mature neurons and neuronal networks. Despite the wealth of information on the action of extracellular cues, little is known about the intrinsic gene regulatory factors that control this developmental decision. Here we report the identification of Prox1, a homeobox transcription factor, as a key player in inhibiting axon elongation. Although Prox1 promotes acquisition of early neuronal identity and is expressed in nascent post-mitotic neurons, it is heavily down-regulated in the majority of terminally differentiated neurons, indicating a regulatory role in delaying axon outgrowth in newly formed neurons. Consistently, we show that Prox1 is sufficient to inhibit neurite extension in neuroblastoma cell lines. Furthermore, shRNA-mediated knock-down of Prox1 in Neuro2A cells induces the extension of neurites. More importantly, Prox1 overexpression suppresses axon elongation in primary neuronal cultures as well as in the developing mouse brain, while Prox1 knock-down promotes axon outgrowth. Mechanistically, RNA-Seq analysis reveals that Prox1 affects critical pathways for neuronal maturation and neurite extension. Interestingly, Prox1 strongly inhibits many components of Ca2+ signaling pathway, an important mediator of axon extension and neuronal maturation. In accordance, Prox1 represses Ca2+ entry upon KCl-mediated depolarization and reduce CREB phosphorylation. These observations suggest that Prox1 acts as a potent suppressor of axon elongation by inhibiting Ca2+ signaling pathway. This action may provide the appropriate time window for nascent neurons to find the correct position in the CNS prior to initiation of axon elongation.

2020-12-31 | GSE158904 | GEO

Prox1 determines hepatocyte versus cholangiocyte cell fate in liver progenitors

Project description:The mammalian liver, the largest solid organ in the body, accomplishes multiple critical roles necessary to preserve homeostasis. Human liver diseases are debilitating, costly and very often result in death. Uncovering developmental mechanisms that establish the complex architecture of the liver or generate the cellular diversity of this organ is necessary to develop more adequate methods to prevent, diagnose and cure liver diseases. This study investigated the role of the homeobox gene Prox1 during mouse hepatogenesis. We used microarrays to detail the global program of gene expression in liver samples from wildtype mice and Prox1 f/f;Foxa3Cre (conditional knockout) mice.

2013-03-15 | E-GEOD-36583 | biostudies-arrayexpress

Comparison of Prox1 expressing and Prox1 knockout intestinal tumors and the effect of A2V+CD40

Project description:Control or A2V+CD40 treated Prox1-proficient (AP) and Prox1-deficient (APP) tumors

2020-02-04 | GSE124716 | GEO

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Project description:Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for adynamic regulation of numerous processes including transcriptional reprograming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation became less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet led to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the preservation of metabolic health.

2023-10-24 | PXD041329 | Pride

Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

Project description:Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells. Microrrays were used to identify gene expression profiles and pathways that are differentially activated after enforced expression of PROX1 in the PROX1-negative human pancreatic ductal adenocarcinoma (PDAC) cell line Capan1. MSCV retroviral transduction was used to generate Capan1 cells that ectopically express PROX1 and selected for puromycin resistance. Three independent transductions with control virus (MSCV_puro) and 3 independent transductions with Prox1-cDNA virus (MSCV_PROX1_puro) were conducted for these experiments.

2016-02-11 | E-GEOD-58547 | biostudies-arrayexpress

An HDAC3-PROX1 Corepressor Module Acts on HNF4α to Control Hepatic Triglycerides

Project description:The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism we developed a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR/HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by Hepatocyte Nuclear Factor 4α (HNF4α). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.

2017-07-26 | GSE90533 | GEO

Transcriptional profile changes by Prox1 expression in thyroid cancer cells

Project description:Human thyroid cancer cell line BCPAP was engineered for doxycyclin-mediated inducible expressoin of Prox1 and next generation sequcing was performed to study the transcriptional regulation by Prox1 BCPAP cells were infected with rTTA2 lentivirus. The resulting cell populations were then stably transfected either with pIRES-hygromycin vector (Clontech) to generate BCPAP-Ctr cells, or with Flag-PROX1-IRES-hygromycin vector to generate BCPAP-Prx cells. PROX1 expression was induced or not in BCPAP-Ctr and BCPAP-Prx cells with 0.5 Âµg/ml doxycycline (Dox) for 48 hours and the total RNA samples were collected for sequencing.

2016-03-02 | E-GEOD-75059 | biostudies-arrayexpress

Characterizing the gene expression profile of Prox1+ intestinal adenoma organoid cells

Project description:We isolated and selected intestinal adenoma organoids from Apcmin/+; Rosa26LSL-TdTomato; Prox1-CreERT2 mice. After the selection procedure without growth factors, we induced CreERT2 activity and the transcription of tdTomato to label Prox1+ cells by 300 nM 4-hydroxytamoxifen for 16h. tdTomato+ (Prox1+) and tdTomato- cells (enriched for Prox1- cells) were FACS sorted and total RNA was isolated.

2018-08-21 | GSE117981 | GEO

Prox1 (Prosper-related homeobox 1) transcription factor depletion effect on CGTH-W-1 cells.

Project description:Analysis of CGTH-W-1 follicular thyroid carcinoma cells transcriptome following 48 hrs siRNA-mediated depletion of PROX1. PROX1 is a homeobox transcription factor. PROX1 depletion decreases migratory ability, motility and invasivness and induces profound cytoskeleton changes of CGTH-W-1 cells. Results provide insight into the role of PROX1 in the thyroid cancer. Three biological replicates for a given condition

2016-07-31 | E-GEOD-80135 | biostudies-arrayexpress

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