ABSTRACT
Coordinated spatio-temporal regulation of the determination and differentiation of neural stem cells is essential for brain development. Failure to integrate multiple factors leads to defective brain structures or tumour formation. Previous studies suggest changes of chromatin state are needed to direct neural stem cell differentiation, but the mechanisms are unclear. Analysis of Snr1, the Drosophila orthologue of SMARCB1, an ATP-dependent chromatin remodelling protein, identified a key role in regulating the transition of neuroepithelial cells into neural stem cells and subsequent differentiation of neural stem cells into the cells needed to build the brain. Loss of Snr1 in neuroepithelial cells leads to premature neural stem cell formation. Additionally, loss of Snr1 in neural stem cells results in inappropriate perdurance of neural stem cells into adulthood. Snr1 reduction in neuroepithelial or neural stem cells leads to the differential expression of target genes. We find that Snr1 is associated with the actively transcribed chromatin region of these target genes. Thus, Snr1 likely regulates the chromatin state in neuroepithelial cells and maintains chromatin state in neural stem cells for proper brain development.
Subject(s)
Drosophila Proteins , Transcription Factors , Animals , Transcription Factors/metabolism , Trans-Activators/genetics , Chromatin Assembly and Disassembly/genetics , Cell Cycle Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila/metabolism , Cell Differentiation/genetics , ChromatinABSTRACT
Nuclear-cytoplasmic localization is an efficient way to regulate transcription factors and chromatin remodelers. Altering the location of existing protein pools also facilitates a more rapid response to changes in cell activity or extracellular signals. There are several examples of proteins that are regulated by nucleo-cytoplasmic shuttling, which are required for Drosophila neuroblast development. Disruption of the localization of homologs of these proteins has also been linked to several neurodegenerative disorders in humans. Drosophila has been used extensively to model the neurodegenerative disorders caused by aberrant nucleo-cytoplasmic localization. Here, we focus on the role of alternative nucleo-cytoplasmic protein localization in regulating proliferation and cell fate decisions in the Drosophila neuroblast and in neurodegenerative disorders. We also explore the analogous role of RNA binding proteins and mRNA localization in the context of regulation of nucleo-cytoplasmic localization during neural development and a role in neurodegenerative disorders.
