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April 5th, 2025
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Kyushu University
neuroscience
biorxiv

MeCP2 controls dendritic morphogenesis via miR-199a-mediated Qki downregulation

Irie, K.Open in Google Scholar•Nakashima, H.Open in Google Scholar•Yamaguchi, M.Open in Google Scholar•Osakada, F.Open in Google Scholar•Ozaki, N.Open in Google Scholar•Nakashima, K.Open in Google Scholar•Tsujimura, K.Open in Google Scholar

Rett syndrome (RTT) (OMIM: 312750) is a severe neurodevelopmental disorder caused by mutations in the MECP2 gene. Although decreased dendritic morphogenesis has been observed in the brain of RTT patients and mouse models, the molecular mechanisms underlying these dendritic anomalies remain unclear. We have previously shown that MeCP2 facilitates specific microRNA (miRNA) processing by associating with the miRNA microprocessor Drosha complex. In this study, we show that MeCP2 positively regulates dendritic formation via miR-199a, a specific target of the MeCP2-Drosha complex. Overexpression of MeCP2 and miR-199a promotes dendritic development such as increases in dendrite length, branching number, and complexity. In contrast, blocking miR-199a inhibited dendrite formation and abolished enhanced dendritic development induced by MeCP2 expression. We also demonstrate that the decreased dendrite outgrowth observed in MeCP2-deficient neurons could be rescued by miR-199a expression. In addition, we found that miR-199a targets the 3\' untranslated region of quaking (Qki), a negative regulator of dendritic development, and downregulates its protein expression level. Furthermore, we report an increase in the Qki protein expression level in miR-199a-2-deficient brains and show that Qki knockdown restores the dendritic morphology of miR-199a-2-Knockout (KO) neurons. Taken together, these results suggest that the MeCP2/miR-199a/Qki axis is critical for proper dendritic development and its dysregulation contributes to the dendritic pathology in RTT.

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