Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency

Abnormal neuronal and synapse growth is a core pathology resulting from deficiency of the Fragile X mental retardation protein (FMRP), but molecular links underlying the excessive synthesis of key synaptic proteins remain incompletely defined. We find that basal brain levels of the growth-suppressor let-7 microRNA (miRNA) family are selectively lowered in FMRP-deficient mice and activity-dependent let-7 downregulation is abrogated. Primary let-7 miRNA transcripts are not altered in FMRP-deficiency and posttranscriptional misregulation occurs downstream of MAPK pathway induction and elevation of Lin28a, a let-7 biogenesis inhibitor. Neonatal restoration of brain let-7 miRNAs corrects hallmarks of FMRP-deficiency, including dendritic spine overgrowth and social and cognitive behavioral deficits, in adult mice. Blockade of MAPK hyperactivation normalizes let-7 miRNA levels in both brain and peripheral blood plasma from Fmr1 KO mice. These results implicate dysregulated let-7 miRNA biogenesis in the pathogenesis
of FMRP-deficiency, and highlight let-7 miRNA-based strategies for future biomarker and therapeutic development.

Keywords: Fragile X Syndrome, Fragile X Mental Retardation Protein, let-7, microRNA biogenesis, microRNA, Lin28, autism spectrum disorder, protein synthesis, gene expression, dendritic spine, behavioral deficits




Subramanian, M, Mills WT IV, Paranjpe MD, Onuchukwu US, Inamdar M, Maytin AR, Li X, Pomerantz JL, Meffert MK