Mirzamohammadi, FatemehKozlova, AnastasiaPapaioannou, GaryfalliaPaltrinieri, ElenaAyturk, Ugur M.Kobayashi, Tatsuya2018-05-302018Mirzamohammadi, Fatemeh, Anastasia Kozlova, Garyfallia Papaioannou, Elena Paltrinieri, Ugur M. Ayturk, and Tatsuya Kobayashi. 2018. “Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models.” Nature Communications 9 (1): 1352. doi:10.1038/s41467-018-03788-7. http://dx.doi.org/10.1038/s41467-018-03788-7.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37067827Feingold 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.en-USJournal Article2018-05-3010.1038/s41467-018-03788-7