Integrative Single-Cell Transcriptomics Reveal Molecular Networks Defining Neuronal Maturation during Postnatal Neurogenesis
Legend: Left: An illustration of coronal section of Nissl-stained adult mouse brain; Confocal images showing that most of DsRed+ (red) cells in DCX-dsRed mouse brains express immature neuron marker doublecortin (DCX, green). Middle: A schematic of the experimental design for single-cell transcriptome analysis. Right: Enrichment heatmap for disease-related genes; Genes showing high levels during the immature phase overlapped significantly with genes implicated in Alzheimer’s and Parkinson’s diseases and genes exhibiting increased levels during neuron maturation overlapped significantly with genes associated with autism.
Citation: Yu Gao, Feifei Wang, Brian E. Eisinger, Laurel E. Kelnhofer, Emily Jobe, and Xinyu Zhao. (2017). Integrative Single-Cell Transcriptomics Reveals Molecular Networks Defining Neuronal Maturation during Postnatal Neurogenesis. Cerebral Cortex, 1;27(3):2064-2077. doi: 10.1093/cercor/bhw040.
Abstract: In the mammalian hippocampus, new neurons are continuously produced from neural stem cells throughout life. This postnatal neurogenesis may contribute to information processing critical for cognition, adaptation, learning, and memory, and is implicated in numerous neurological disorders. During neurogenesis, the immature neuron stage defined by doublecortin (DCX) expression is the most sensitive to regulation by extrinsic factors. However, little is known about the dynamic biology within this critical interval that drives maturation and confers susceptibility to regulatory signals. This study aims to test the hypothesis that DCX-expressing immature neurons progress through developmental stages via the activity of specific transcriptional networks. Using single-cell RNA-seq combined with a novel integrative bioinformatics approach, we discovered that individual immature neurons can be classified into distinct developmental subgroups based on characteristic gene expression profiles and subgroup-specific markers. Comparisons between immature and more mature subgroups revealed novel pathways involved in neuronal maturation. Genes enriched in less mature cells shared significant overlap with genes implicated in neurodegenerative diseases, while genes positively associated with neuronal maturation were enriched for autism-related gene sets. Our study thus discovers molecular signatures of individual immature neurons and unveils potential novel targets for therapeutic approaches to treat neurodevelopmental and neurological diseases.
About the Lab: Research in the Zhao laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neurodevelopment with the goal of applying this knowledge for the treatment of neurological disorders and injuries. Neurodevelopmental disorders are a highly heterogeneous constellation of disorders, both in terms of etiology and clinical manifestations. Using neural stem cells as model systems, the lab is investigating the molecular mechanisms that regulate neuronal development during the postnatal period and their implications in human neurodevelopmental disorders such as Rett Syndrome, autism, and fragile X syndrome.