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SHP-2 deletion in CD4Cre expressing chondrocyte precursors leads to tumor development with wrist tropism.

ABSTRACT: Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.

SUBMITTER: McNamara JT

PROVIDER: S-EPMC8501018 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to pituitary dysfunction, neurodegeneration and development of obesity.

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DOT1L deletion impairs the development of cortical parvalbumin-expressing interneurons.

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Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to neurodegeneration and development of obesity

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.

2012-11-16 | GSE38672 | GEO

Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to neurodegeneration and development of obesity

2012-11-16 | E-GEOD-38672 | biostudies-arrayexpress

Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice.

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Project description: Not available

| S-EPMC10955195 | biostudies-literature

Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice.

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Project description:BackgroundAdipocytokines play a pivotal role in maintaining adipose tissue homeostasis by regulating cellular metabolism, proliferation, differentiation, and secretory activity. These soluble factors are relevant components for healthy adipose tissue, while their deficiency is closely associated with the development of obesity and related metabolic diseases, e.g., chronic inflammation. In human adipose tissue, inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is expressed in proportion to the development of adipose tissue, i.e., the individual's BMI. Thus, ITIH5 has been proposed to be an inert marker of human obesity. However, when applied to adipose stem cells in vitro, recombinant (r)ITIH5 protein inhibited proliferation and adipogenesis, suggesting that ITIH5 negatively affects the development of fat mass. We now tested the role of ITIH5 in vivo and compared ITIH5+/+ wildtype with ITIH5-/- knockout mice.ResultsGenetic deletion of ITIH5 significantly increased adipose tissue mass relative to animal bodyweight (p < 0.05). Next, we characterized adipose stem cells (ASCs) from both genotypes in vitro. ITIH5-/- cells exhibited increased proliferation and adipogenic differentiation (p < 0.001), which could explain the increase in adipose tissue in vivo. Furthermore, ASCs from ITIH5-/- animals were more responsive to stimulation with inflammatory mediators, i.e., these cells released greater amounts of IL-6 and MCP-1 (p < 0.001). Importantly, the application of the rITIH5 protein reversed the observed knockout effects in ASCs.ConclusionsOur data suggest that ITIH5 potently regulates adipose tissue development and homeostasis by modulating ASC biology in mice. In addition, the effect of the rITIH5 protein underscores its potential as a therapeutic agent to correct the adipose tissue dysregulation often associated with obesity and metabolic disorders.

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