A role for the cancer-associated miR-106b~25 cluster in neuronal stem cells

摘要: In the last decade, micro-RNAs (miRNAs) have emerged as major regulators of cell fate. They are involved in fine-tuning gene expression normal developing tissues and often aberrantly expressed different disease states, including cancer. miRNAs 20-25 nucleotide non-coding RNAs that repress translation stability a large number target mRNAs. The study by Brett et al previous issue AGING adds to our understanding how regulate differentiation adult neural stem cells (NSCs) [1]. The authors used primary cultures stem/progenitor (NSPCs) isolated from mice investigate importance specific miRNA cluster, miR-106b~25, regulating proliferative potential NSCs. This cluster is located within an intronic region Mcm7 codes for three species, miR-106b, miR-93 miR-25. Interestingly, activation this has been observed tumour types inhibition anti-proliferative pro-apoptotic genes, such p21, Bim TGF-beta [2,3]. Furthermore, overexpressed prostate cancer where it downregulation PTEN also cooperates with its host drive tumourigenesis [4]. The current shows miR-106b~25 present self-renewing NSPCs does not change when stimulated undergo differentiation. Among miR-25 seems be most important maintaining proliferation NSPC. Overexpression either miR-25, or whole induced increased proportion positive neuronal marker Tuj1. Micro-RNAs key proliferation, self-renewal both embryonic [5]. Embryonic deplete Dicer, essential component processing machinery, fail induce upon induction vitro [6]. during transition progenitors neurons [7]. Some genes neurogenesis identified, but complex regulatory networks, involving negative feedback loops, remains elucidated. Brett al. bioinformatics approach identify targets found over-representation insulin/IGF/Akt signalling pathways. pathway inhibits activity members O-subfamily forkhead-box containing transcription factors, which survival [8]. There clear evidence FOXO factors maintenance. Deletion FOXO3a alone, combined deletion FOXO1, FOXO4, results decreased NSCs vivo, reduces their capacity [9,10]. One showed loss function causes Wnt increases short-term [10]. Another regulates several associated hypoxia response, cycle regulation metabolism, was able detect binding promoters p27 Ddit4 [9]. Brett site (FHRE) first intron moreover, discovered overexpression constitutively active mutant resulted reporter construct carrying genomic region. However, they investigated encoded wild type FOXO3a-null mice, found, somewhat surprisingly, rather than decreased. result suggests interrelationship between transcriptional locus embedded it. FOXO3a shown regulator types. For example, can miR-21, suppressor Fas Ligand (FasL) human lung [11], miR-155 contributes survival, growth resistance chemotherapy breast [12]. possible explanation why FOXO3-null did display reduction miR106~25 could compensation other family members, FOXO1. Also, FoxO3a dependent on recapitulating exact physiological setting encountered hypoxic conditions niche. Then again, indirect. N-Myc oncogene neuroblastoma [13]. Several studies inhibit Myc through mechanisms, micro-RNA mediated [14,15,16]. It interesting whether cluster. There now increasing maintenance part collection functions related aging. particularly compelling light identification single polymorphisms (SNPs) show strong association longevity [17]. balance stress resistance, many Disrupting likely detrimental consequences, contribute states. Understanding role biology will basic process aging, well age-related diseases, 2 diabetes, Alzheimer's