MicroRNA miR-137 Regulates Neuronal Maturation by Targeting Ubiquitin Ligase Mind Bomb-1

Abstract

A final step of neurogenesis is the maturation of young neurons, which is regulated by complex mechanisms and dysregulation of this process is frequently found in neurodevelopmental disorders. MicroRNAs have been implicated in several steps of neuronal maturation including dendritic and axonal growth, spine development, and synaptogenesis. We demonstrate that one brain-enriched microRNA, miR-137, has a significant role in regulating neuronal maturation. Overexpression of miR-137 inhibits dendritic morphogenesis, phenotypic maturation, and spine development both in brain and cultured primary neurons. On the other hand, a reduction in miR-137 had opposite effects. We further show that miR-137 targets the Drosophila Mib1 protein through the conserved target site located in the 3′ untranslated region of Mib1 mRNA. Mib1 is an ubiquitin ligase known to be important for neurodevelopment. We show that exogenously expressed Mib1 could partially rescue the phenotypes associated with miR-137 overexpression. These results demonstrate a novel miRNA-mediated mechanism involving miR-137 and Mib1 that function to regulate neuronal maturation and dendritic morphogenesis during development.

Impact of a microRNA MIR137 Susceptibility Variant on Brain Function in People at High Genetic Risk of Schizophrenia or Bipolar Disorder

“…At present there is a rather limited literature. It is considered to be enriched in neurones, particularly, in the dentate gyrus and it is thought to have multiple functions during different stages of neurodevelopment (Shi et al, 2010;Smrt et al, 2010;Szulwach et al, 2010). Two recent molecular studies indicate MIR137 is involved in multiple epigenetic mechanisms regulating the balance of neuronal proliferation and differentiation (Sun et al, 2011;Smrt et al, 2010;Szulwach et al, 2010).…”

“…Indeed, postmortem studies have indicated differential expression levels of several miRNAs in prefrontal regions in SCZ and BD vs healthy controls (Perkins et al, 2007;Forero et al, 2010;Kim et al, 2010;Beveridge et al, 2011). In terms of MIR137 specifically, normal levels of expression are required for regulating the balance of neuronal proliferation and differentiation (Sun et al, 2011;Shi et al, 2010;Smrt et al, 2010;Szulwach et al, 2010). Although the expression pattern has yet to be fully established, it is enriched in neurons, particularly in the dentate gyrus, a region implicated in psychiatric disorders and known to undergo neurogenesis into adulthood (Sempere et al, 2004;Smrt et al, 2010).…”

“…In terms of MIR137 specifically, normal levels of expression are required for regulating the balance of neuronal proliferation and differentiation (Sun et al, 2011;Shi et al, 2010;Smrt et al, 2010;Szulwach et al, 2010). Although the expression pattern has yet to be fully established, it is enriched in neurons, particularly in the dentate gyrus, a region implicated in psychiatric disorders and known to undergo neurogenesis into adulthood (Sempere et al, 2004;Smrt et al, 2010). It is also notable that genes associated with SCZ, including TCF4, CACNA1C, and c10orf26, are also targets of MIR137 (Ripke et al, 2011).…”

“…We also report other brain regions that reached significance at the whole brain level (Phillips et al, 2003;Smrt et al, 2010;Szulwach et al, 2010). We examined whether there were differences in activation according to MIR137 genotype across all groups, and whether there were diagnosis-specific differences in genotype between the groups.…”

MicroRNA-137 Is a Novel Hypoxia-responsive MicroRNA That Inhibits Mitophagy via Regulation of Two Mitophagy Receptors FUNDC1 and NIX

“…The downregulated expression of miR-137 in brain cancer stem cells is necessary for self-renewal in glioma stem cells (33,34). miR-137 regulates neuronal maturation by targeting ubiquitin ligase Mind Bomb-1 (35). miR-137 is also down-regulated in the blood serum of Alzheimer disease patients (36).…”