Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder mostly in females, mainly caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Although initial observations had suggested that RTT patients appear relatively normal at birth and during very early stages of development, increasing evidence suggests early developmental delays in RTT patients. Previously, we have found that MeCP2 regulates the processing of specific microRNAs as a component of the Drosha complex and identified miR-199a as a MeCP2 target. We found that MeCP2/miR-199a axis regulates neural stem/precursor cell (NS/PC) differentiation, with the balance tipped toward differentiation into astrocytes in MeCP2-deficient NS/PC. We also indicated that this imbalance of differentiation is caused by the augmentation of BMP signaling, which is known to inhibit and promote neuronal and astrocytic differentiation, respectively.

Substantial evidence has shown that morphological and functional abnormalities of neurons are involved in RTT pathogenesis, therefore, it has been considered that symptoms of RTT are attributed to neuron-intrinsic dysfunction in the patients. However, increasing evidence has suggested that glial abnormalities associated with the pathogenesis of RTT, e.g., aberrant activation of microglia, brain-resident immune cells resembling macrophage, has been observed in MeCP2-KO mice, whereas the underlying mechanisms still remain unknown. Previously, it has been shown that the expression of retrotransposon LINE1 (L1) and the retro-transposition of its reverse transcript (cDNA) into the genome are increased in MeCP2-KO mouse brains. Furthermore, it has been shown that endogenous DNAs activate microglia in the brain via DNA-recognizing Toll like receptor 9 (TLR9). Considering these findings, we hypothesized that L1cDNA-TLR9-microglial activation pathway could participate in the onset of RTT. To examine

this hypothesis, we crossed MeCP2-KO mice with TLR9-KO mice, leading to extending life span and ameliorating RTT symptoms in MeCP2-KO mice. Moreover, treatments of MeCP2-KO mice with reverse transcriptase inhibitors to prevent L1 cDNA synthesis prolonged the longevity and alleviated RTT symptoms. Altogether, these findings suggest the involvement of endogenous DNA-TLR9-microglial activation axis in the RTT pathogenesis and may pave the way for the development of therapeutic strategies for this complex and devastating developmental disease.

Reference:
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2. Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, Itoh M, Uesaka M, Imamura T, Nakahata Y, Yamashita Y, Abe T, Takamori S, Nakashima K. miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes. Cell Rep, 12, 1887-1901, 2015

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