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.
Highlights
Heterozygous mutations in MYCN or MIR17HG in humans cause Feingold syndrome that is characterized by skeletal developmental defects including microcephaly, short stature, and brachysyndactyly with diminished middle phalanxes[1,2,3]
We show that overactivation of TGFβ signaling causes the skeletal defects of miR-17-92 miRNAdeficient limbs and the skull, whereas downregulation of phosphoinositide 3-kinase (PI3K)/ Akt signaling is a major contributor to the skeletal phenotype caused by Mycn-deficiency
Since Mycn deficiency reduces limb bud cell proliferation[15], these findings suggest that similar cellular mechanisms underlie the pathogenesis of Feingold syndrome type 1 and type 2
Summary
Heterozygous mutations in MYCN or MIR17HG in humans cause Feingold syndrome that is characterized by skeletal developmental defects including microcephaly, short stature, and brachysyndactyly with diminished middle phalanxes[1,2,3]. Based on the fact that deletion of either MYCN or Mir17HG results in similar skeletal defects in humans and that miR-17-92 expression is regulated by Myc transcription factors, it has been hypothesized that Mycn and miR-17-92 miRNAs function in the same pathway to regulate skeletal development[2]. To test this hypothesis, we conditionally deleted Mir[17-92] with or without deletion of Mir106b-25 in the developing limb bud and skull mesenchyme. This study using in vivo models suggests that physiological effects of miRNAs and transcription factors, which regulate multiple genes, converge onto relatively limited signaling pathways
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