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

Fatemeh Mirzamohammadi, Anastasia Kozlova, Garyfallia Papaioannou, Elena Paltrinieri, Ugur M. Ayturk and Tatsuya Kobayashi ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03788-7

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