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

被引：14

作者：

Mirzamohammadi, Fatemeh ^{[1
,2
]}

Kozlova, Anastasia ^{[1
,2
]}

Papaioannou, Garyfallia ^{[1
,2
]}

Paltrinieri, Elena ^{[1
,2
]}

Ayturk, Ugur M. ^{[3
]}

Kobayashi, Tatsuya ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA

[2] Harvard Med Sch, Boston, MA 02114 USA

[3] Hosp Special Surg, Musculoskeletal Integr Program, 535 E 70th St, New York, NY 10021 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

PROTEIN-KINASE CK2; N-MYC; CRE RECOMBINASE; C-MYC; EXPRESSION; PTEN; MICE; SKELETAL; DISEASE; CLUSTER;

D O I：

10.1038/s41467-018-03788-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-beta signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-beta signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-beta 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-beta inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.

引用

页数：10