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Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models

Author

Listed:
  • Fatemeh Mirzamohammadi

    (Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School)

  • Anastasia Kozlova

    (Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School)

  • Garyfallia Papaioannou

    (Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School)

  • Elena Paltrinieri

    (Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School)

  • Ugur M. Ayturk

    (Musculoskeletal Integrity Program, Hospital for Special Surgery)

  • Tatsuya Kobayashi

    (Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School)

Abstract

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.

Suggested Citation

  • Fatemeh Mirzamohammadi & Anastasia Kozlova & Garyfallia Papaioannou & Elena Paltrinieri & Ugur M. Ayturk & Tatsuya Kobayashi, 2018. "Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03788-7
    DOI: 10.1038/s41467-018-03788-7
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