Researchers at Kyushu University discovered a possible genetic cause for Rett syndrome's neurological dysfunction. Researchers discovered that the neural stem cells responsible for the disease are defective in key genes. This causes the cells to produce fewer neurons and more astrocytes, the brain's maintenance cells.Researchers hope that their molecular pathology, which was published in Cell Reports, will lead to future therapeutic targets for Rett syndrome.Rett syndrome, a progressive neurodevelopmental disorder, is found in approximately one in 10,000 to 15,000 female babies. It causes impairments in cognition as well as coordination. It is not easy to identify at first, as children seem to grow normally within the first six to 18 months."Rett syndrome is caused methyl-CpG binding Protein 2 (or MeCP2) mutations." Hideyuki Nakashima, a Kyushu University Faculty of Medical Sciences' first author, explained that the gene was discovered over 20 years ago. Although much has been done since then, it remains to be determined how the mutations lead to the disease.The team previously discovered that MeCP2 is a regulator of the processing of microRNAs. This regulates the function of neurons. They decided to revisit the topic and see if this pathway is also involved in neural stem cell differentiation.MicroRNAs, or miRNAs, are smaller than messenger RNA. They are the final template that is transcribed from DNA and used by cells to synthesize protein.Nakashima says, "We found many microRNAs that were associated with MeCP2, but only one of them affected the differentiation and stem cell differentiation: a microRNA named miR-199a." "In fact, when either MeCP2 nor miR-199a is disrupted, it increases the production of cells known as astrocytes."Astrocytes can be described as the support cells for your brain. Astrocytes are the support cells of your brain. While neurons generate electrical signals, they also help to maintain all other parts. The same stem cells that produce neurons and astrocytes are used to develop them. Their production is controlled. These stem cells can produce more neurons if they are deficient in MeCP2 and miR-199a.Further analysis revealed that miR199a targets Smad1, which is a transcription factor essential for proper cell development. Nakashima states that Smad1 is a downstream function of BMP signaling. This pathway is known to inhibit the formation of neurons and promote the creation of astrocytes.The team created a brain organoid cell culture to further investigate the phenomenon. This is a 3D culture of neural cells grown from iPS cells derived directly from Rett syndrome patients. The team was able reduce abnormal neural stem cell differentiation by inhibiting BMP (breast morphogenetic protein).Kinichi Nakashima who led the team, said that "our findings have given us valuable insights into the role MeCP2, miR199a and BMP signaling" in the pathology associated with Rett syndrome. We hope that this will lead to clinical treatments of Rett syndrome symptoms. However, further investigation is necessary.
