The role of skull bone marrow-derived CNS macrophages in Rett syndrome.

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PROJECT SUMMARY Rett syndrome is a devastating neurodevelopmental disorder with a significant burden on patients and their families. Patients present with an initial period of healthy neurological development, immediately followed by severe motor and cognitive regression during their first few years of life. Patients typically suffer from gait impairments, loss of speech, seizures, and sleep disturbances. Owing to its primarily neurological presentation, this X-linked disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) has been mostly studied as a disease of neurons. While MeCP2 loss results in cell-intrinsic neuronal dysfunction, non-neuronal mechanisms also impact Rett syndrome progression, thus opening therapeutic avenues that bypass manipulation of neurons. Research over the past decade has shed light on neuroimmune interactions at the borders of the brain that are critical for healthy brain development and function, suggesting the possibility to uncover new mechanisms contributing to Rett syndrome. One major advance in the field of neuroimmunology has been the discovery of the meningeal lymphatic network. Meningeal lymphatic vessels reside in the brain’s outer membranous layer, the dura mater, where they regulate central nervous system (CNS) fluid volume and the continuous clearance of cerebrospinal fluid (CSF) out of the CNS. Ablation of these vessels impairs CSF clearance, resulting in extracellular waste accumulation and cognitive impairment. The clinical presentation of seizures, increased CSF volume, and inflammatory changes to the composition of CSF in Rett patients, suggests a potential impairment in the perfusion and clearance of the CSF that normally bathes the brain. Supporting this hypothesis, our preliminary data shows that CSF perfusion throughout the brain, as well as a major regulator of normal CSF dynamics, the meningeal lymphatics, is largely absent in an MeCP2-deficient mouse model of Rett syndrome. Here, we propose to test the hypothesis that the loss of meningeal lymphatics, resulting from a loss of meningeal macrophages, is an important contributor to Rett syndrome. Our preliminary data suggest that this decreased meningeal lymphatic coverage may result indirectly from the loss of meningeal macrophages, which typically provide trophic support to lymphatic vessels. Our data also points to an upstream, cell-intrinsic impairment in bone marrow hematopoiesis, or immune cell production, as the mechanism responsible for the observed loss in meningeal macrophages. The first aim will employ state-of-the-art transgenic mouse lines to study the cell type specific effects of MeCP2 loss on skull bone marrow hematopoiesis and macrophage differentiation. The second aim will employ advanced cell replacement strategies and viral overexpression tools to assess the functional relationship, as well as therapeutic potential, of meningeal macrophages and lymphatics in Rett syndrome. This work has the potential to both uncover new biology that is critical to Rett syndrome progression and identify new and accessible therapeutic targets to help ameliorate disease.