let-7 and miR-140 microRNAs coordinately regulate skeletal development

Abstract

Significance A global reduction of microRNAs (miRNAs) in growth plate chondrocytes results in defects in both proliferation and differentiation; however, specific miRNAs that regulate these processes have not been identified. In this study, we provide evidence that let-7 miRNAs and microRNA-140 (miR-140), among other miRNAs, play major roles in endochondral bone development. We found that suppression of let-7 miRNAs in chondrocytes reduced proliferation, whereas the chondrocyte-specific miR-140 was necessary for differentiation into proliferating chondrocytes. Deficiency of both let-7 and miR-140 caused a dramatic growth defect, synergistically reducing proliferating chondrocyte mass. Thus, these miRNAs coordinately regulate distinct steps of endochondral bone development.

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…Unlike mature let-7, which is undetectable in early embryos and embryonic stem cells, but becomes highly expressed in most adult tissues, the RNA binding protein Lin28a is abundantly expressed in stem cells and cancer cells, and binds to the loop region of pri-let-7 and pre-let-7 miRNA transcripts to inhibit their processing into mature let-7 as well as to facilitate their degradation. Therefore, let-7 repression is commonly seen as a consequence of Lin28a overexpression (Jiang and Baltimore, 2016;Papaioannou et al, 2013;Schulman et al, 2005;, and Lin28a overexpression has provided a novel way to suppress the endogenous levels of all let-7 family members. Our data show that while Lin28a overexpression affected both TD and TI antigen-induced IgM production, deletion of the let-7adf cluster only altered TI antigen-induced IgM, suggesting that the let-7-independent functions of Lin28a may contribute to the observed phenotype in response to TD antigen challenge.…”

“…The Lin28a iTg mice have been described by Dr. Tatsuya Kobayashi (Massachusetts General Hospital) (Papaioannou et al, 2013). The let-7adf cluster KO mice and the let-7bc cluster KO mice were gifts from Dr. George Daley (Harvard Medical School) and Dr. Antony Rodriguez.…”

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

“…Let-7 family members function in combination to affect both early and late developmental timing decisions 34 and are involved in organ development by regulating TGFb-R1 and E2F5. 35,36 Mlin41 is a let-7 target gene in mouse neural tube closure, suggesting that Hlin41 might be a potential human development gene. 37 HMGA2 is an effector that is involved in the genetic switch wherein let-7 activation in the fetal state causes a shift toward an adult-like myeloid-dominant output.…”

MicroRNAs and post-transcriptional regulation of skeletal development

“…Of all the miRNAs affecting chondroblast differentiation, miR-140 has received the most research attention to date (He et al 2009, Nakamura et al 2011, Gibson & Asahara 2013, Karlsen et al 2013, Papaioannou et al 2013). The results of these studies indicate that miR-140 is one of the main regulators of chondroblast differentiation through its effects on the expression of not only Sox9 (Karlsen et al 2013), but also several other targets (Hdac4, Sp1, Smad3, and aggrecan) (Pais et al 2010, Nakamura et al 2011, Karlsen et al 2013.…”