Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. We have previously reported that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs) as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that expression of miR-199a rescues several impairments in MeCP2-deficient neurons, including reductions in soma size, excitatory neurotransmission and synaptic formation, which are hallmarks of RTT neuropathology. We here show that the MeCP2/miR-199a axis is participated not only in the regulation of neuronal functions but also in the fate specification of neural stem cells (NSCs). Expression of MeCP2 in NSCs promoted neuronal differentiation, while it inhibited astrocyte differentiation. Furthermore, this effect of MeCP2 was cancelled by inhibition of miR-199a. Based on the results of database search, we identified Smad1 as a target molecule of miR-199a. Smad1 is a well-known critical transcription factor downstream of bone morphogenetic protein signaling, which promotes and inhibits astrocytic and neuronal differentiation of NSCs, respectively. Consistent with these findings, we observed that Smad1 protein expression is increased in MeCP2 deficient mouse brain, in which miR-199a expression is decreased by the loss of MeCP2 expression. We further found that astrocyte differentiation of NSCs is indeed enhanced in MeCP2 deficient brain, corresponding to the fact that protein levels of typical astrocyte marker glial fibrillary acidic protein is increased in RTT patient. Since it is becoming apparent that functions of MeCP2 in glial cells are also involved in the pathogenesis of RTT, our finding implies that imbalance of neuronal and glial differentiation can be one of the causes for RTT.
