| First Author | Subramanian M | Year | 2024 |
| Journal | iScience | Volume | 27 |
| Issue | 1 | Pages | 108676 |
| PubMed ID | 38235335 | Mgi Jnum | J:344338 |
| Mgi Id | MGI:7575372 | Doi | 10.1016/j.isci.2023.108676 |
| Citation | Subramanian M, et al. (2024) Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency. iScience 27(1):108676 |
| abstractText | 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. |
