Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway

Abstract

Fragile X syndrome is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes. Recently, mRNA ligands associated with FMRP have been identified. However, the mechanism by which FMRP regulates the translation of its mRNA ligands remains unclear. MicroRNAs are small noncoding RNAs involved in translational control. Here we show that in vivo mammalian FMRP interacts with microRNAs and the components of the microRNA pathways including Dicer and the mammalian ortholog of Argonaute 1 (AGO1). Using two different Drosophila melanogaster models, we show that AGO1 is critical for FMRP function in neural development and synaptogenesis. Our results suggest that FMRP may regulate neuronal translation via microRNAs and links microRNAs with human disease.

Expanding the ‘central dogma’: the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia

“…86 The possible role of miRNA in the etiology of fragile X syndrome is suggested in an animal model that found the etiologic fragile X mental retardation protein to regulate synaptic plasticity via a mechanism that involves miRNAs. 87 To date there is no evidence linking ncRNAs and schizophrenia, and so the examples provided above are highly speculative. However, elucidation of the genetic information that controls (directly or indirectly) the rate of protein synthesis might be fundamental to understanding disease expression, especially with neurodevelopmental diseases.…”

Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease?

“…49,50 This was also confirmed for mammalian FMRP in vivo. 51 Loss or mutation of survival of motor neuron protein (SMN), a component of an miRNA containing ribonucleoprotein (RNP) complex, is thought to be the cause of spinal muscular atrophy (SMA), a disease characterized by the progressive degeneration of motor neurons. 23 SMN binds to Gemin3 in a RNP complex also consisting of Gemin4, eIF2C2 and various miRNAs.…”

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

“…Drosophila FMRP associates with an RNA-induced silencing complex (RISC), through which cells destroy specific transcripts, and is also involved in microRNA pathways of translational repression [Caudy et al, 2002;Ishizuka et al, 2002;Schenck et al, 2003;Jin et al, 2004]. These studies led to the finding that mammalian FMRP associates with the microRNA pathway [Jin et al, 2004].…”