Researchers have revealed how dysregulation of the MECP2/miR-199a axis may contribute to the molecular pathology of Rett syndrome.
Rett syndrome (RTT) is a progressive neurodevelopmental disorder that impairs brain development. It primarily affects females, and results in cognitive deficits and gradual decline of motor function in patients after 6-18 months of age. Unfortunately, there is currently no known cure for RTT.
RTT arises from loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. MECP2 is an epigenetic regulator known to be vital for neuronal maturation and differentiation. In neuronal stem/precursor cells (NS/PCs), MECP2 expression normally suppresses astrocytic differentiation in favour of neuronal differentiation. In contrast, NS/PCs derived from RTT patients exhibit a preference for astrocytic differentiation.
MECP2 has previously been demonstrated to facilitate post-transcriptional processing of miR-199a, a miRNA regulating neuronal function. Until recently, the role of MECP2 and miR-199a in NS/PC differentiation has not been explored.
The MECP2/miR-199a axis and neuronal differentiation
A recent paper, published in Cell Reports, revealed that MECP2 and miR-199a may act together to regulate neuronal differentiation. Researchers observed an increase of neuronal cells and a decrease of astrocytes in the hippocampi of both MECP2 and miR-199a knockout mice. This suggests that perturbations in the MECP2/miR-199a axis skews NS/PC differentiation from neuronal to astrocytic. In MECP2 knockouts, miR-199a expression rescued abnormal NS/PC differentiation in MECP2 knockouts. This finding implicates miR-199a as a downstream target of MECP2.
The researchers also found that miR-199a targets and interferes with SMAD1 expression. SMAD1 mediates bone morphogenetic protein (BMP) signalling by acting as a downstream transcription factor. BMP signalling influences NS/PC fates by inhibiting neuronal differentiation and promoting astrocyte differentiation.
Altogether, these results suggest that MECP2 suppresses SMAD1 via miR-199a interference. As a result, MECP2 and miR-199a deficiency may lead to overexpression of SMAD1 and BMP signalling, which ultimately leads to impaired brain development in RTT patients.
A novel therapeutic strategy for Rett syndrome
In the study, brain organoids were also used as models to investigate the role of BMP signalling in RTT pathogenesis. These were generated using induced pluripotent stem cells derived from patients. Researchers observed significant growth reductions, upregulated BMP signalling and impaired NS/PC differentiation in the RTT organoids. These phenotypes were ameliorated following the administration of BMP inhibitors.
These observations have not only supported dysregulation of the MECP2/miR-199a/SMAD1 axis in RTT pathogenesis. But they have also pointed to a novel therapeutic target that may eventually lead to efficacious RTT treatments.
Image credit: MasterTux – Pixabay
