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Mirzamohammadi, Fatemeh

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Mirzamohammadi

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Fatemeh

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Mirzamohammadi, Fatemeh

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2016 - 20183

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Author's Publications: search.filters.isAuthorOfPublication.20fabfec-0261-4b71-a9f7-622dd1c589f0

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Now showing 1 - 3 of 3
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    Polycomb repressive complex 2 regulates skeletal growth by suppressing Wnt and TGF-β signalling
    (Nature Publishing Group, 2016) Mirzamohammadi, Fatemeh; Papaioannou, Garyfallia; Inloes, Jennifer B.; Rankin, Erinn B.; Xie, Huafeng; Schipani, Ernestina; Orkin, Stuart H.; Kobayashi, Tatsuya
    Polycomb repressive complex 2 (PRC2) controls maintenance and lineage determination of stem cells by suppressing genes that regulate cellular differentiation and tissue development. However, the role of PRC2 in lineage-committed somatic cells is mostly unknown. Here we show that Eed deficiency in chondrocytes causes severe kyphosis and a growth defect with decreased chondrocyte proliferation, accelerated hypertrophic differentiation and cell death with reduced Hif1a expression. Eed deficiency also causes induction of multiple signalling pathways in chondrocytes. Wnt signalling overactivation is responsible for the accelerated hypertrophic differentiation and kyphosis, whereas the overactivation of TGF-β signalling is responsible for the reduced proliferation and growth defect. Thus, our study demonstrates that PRC2 has an important regulatory role in lineage-committed tissue cells by suppressing overactivation of multiple signalling pathways.
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    Ras signaling regulates osteoprogenitor cell proliferation and bone formation
    (Nature Publishing Group, 2016) Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Kobayashi, Tatsuya
    During endochondral bone development, osteoblasts are continuously differentiated from locally residing progenitor cells. However, the regulation of such endogenous osteoprogenitor cells is still poorly understood mainly due to the difficulty in identifying such cells in vivo. In this paper, we genetically labeled different cell populations of the osteoblast linage using stage-specific, tamoxifen-inducible Cre transgenic mice to investigate their responses to a proliferative stimulus. We have found that overactivation of Kras signaling in type II collagen-positive, immature osteoprogenitor cells, but not in mature osteoblasts, substantially increases the number of their descendant stromal cells and mature osteoblasts, and subsequently increases bone mass. This effect was mediated by both, the extracellular signal-regulated kinase (ERK) and phosphoinositide 3 kinase (PI3K), pathways. Thus we demonstrate that Ras signaling stimulates proliferation of immature osteoprogenitor cells to increase the number of their osteoblastic descendants in a cell-autonomous fashion.
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    Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
    (Nature Publishing Group UK, 2018) Mirzamohammadi, Fatemeh; Kozlova, Anastasia; Papaioannou, Garyfallia; Paltrinieri, Elena; Ayturk, Ugur M.; Kobayashi, Tatsuya
    Feingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-β signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-β signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn-deficiency is partially rescued by Pten heterozygosity, but not by TGF-β inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.