Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by a wide range of neurological deficits including, seizures, movement disorders, autonomic dysfunction, and marked breathing abnormalities. Nearly all cases of RTT are caused by de novo mutations in Methyl-CpG-binding protein 2 (MECP2), which functions as a global regulator of gene transcription. MeCP2 is highly expressed throughout the nervous system, and because the clinical features are associated with neuronal function, RTT has typically been assumed to be a disease of neurons. However, recent work has challenged this view, indicating that other cells within the nervous system such as astrocytes and microglia may play an important role in the pathogenesis of disease. While astrocytes directly contribute to key phenotypes associated with RTT, such as breathing and glucose sensitivity, the consequences of loss of MeCP2 on specific astrocyte sub-populations in these key regions remains completely undefined. Astrocytes have long been considered to be a uniform cell type, and in spite of recent findings indicating they perform diverse roles across the CNS, the nature of their cellular and functional heterogeneity remains shrouded in mystery. Using the brainstem and RTT as models for decoding these cellular and functional relationships, we hypothesize that MeCP2 plays a crucial role in key astrocyte subtypes within the brainstem, a brain region we have previously demonstrated to be critical in the genesis of breathing and other physiological abnormalities in RTT. To this end we have used FACS-based approaches to identify unique subpopulations of astrocytes in the adult brainstem.
In specific aim 1 of this proposal, we will validate the presence of these populations in the brainstem and perform gene expression profiling on each subpopulation to decode their unique molecular signature.
In specific aim 2 we will use similar FACS-based approaches to delineate astrocyte heterogeneity and their underlying molecular profiles in the brainstem of the RTT mouse. Through this work we will determine brainstem astrocyte heterogeneity and define the molecular profiles of these cells in normal and MeCP2 mutant populations, lending unprecedented insight into the nature of astrocyte heterogeneity in health and disease.
This project focuses on delineating astrocyte heterogeneity in the normal and RTT brainstem. Knowledge gained from these studies will provide needed insight into the cellular heterogeneity of astrocytes in the brain and how their dysregulation contributes to key physiological phenotypes manifest in neurological disease. The approaches, paradigms, and findings of this study will have broad applications in understanding both normal brain function and neurological disease, as astrocytes are the most abundant cell type in the CNS and are implicated in a host of other neurological diseases, including: Autism, Epilepsy, Schizophrenia, ALS, MS, and Alzheimer's.
| John Lin, Chia-Ching; Yu, Kwanha; Hatcher, Asante et al. (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396-405 |
| Zhu, Wenyi; Krishna, Saritha; Garcia, Cristina et al. (2017) Daam2 driven degradation of VHL promotes gliomagenesis. Elife 6: |
| Ma, Mandy; Adams, Heather R; Seltzer, Laurie E et al. (2016) Phenotype Differentiation of FOXG1 and MECP2 Disorders: A New Method for Characterization of Developmental Encephalopathies. J Pediatr 178:233-240.e10 |
