Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency
Megha Subramanian,
William T. Mills, IV,
Manish D. Paranjpe,
Uche S. Onuchukwu,
Manasi Inamdar,
Amanda R. Maytin,
Xinbei Li,
Joel L. Pomerantz,
Mollie K. Meffert
Affiliations
Megha Subramanian
Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
William T. Mills, IV
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Manish D. Paranjpe
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
Uche S. Onuchukwu
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Manasi Inamdar
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Amanda R. Maytin
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Xinbei Li
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Joel L. Pomerantz
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Mollie K. Meffert
Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Summary: 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.
