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How two proteins regulate and maintain neurons
The work by Salk Institute scientists was published in Cell Stem Cell on September 14, 2017. It offers a look into how and why an imbalance between these proteins might contribute to mental illness or age-related brain diseases.
"Increasingly, we are learning that diseases like schizophrenia, depression and Alzheimer's all have a cellular basis. So we are eager to understand how specific brain cells develop, what keeps them healthy, and why advancing age or other factors can lead to disease."
In 1998, Gage led a research team which discovered adult brains do produce new neurons, contrary to decades of dogma saying we are born with all the neurons we will ever have. Since then, he has been finding out and explaining various aspects of neurogenesis, as well as what goes wrong in various neurological disorders. In 2015, his lab identified a cellular basis for bipolar disorder.
His new research investigates how neural precursor cells maintain cell identity even while dividing to produce neurons or astrocytes. Gage's team already knew that each cell nucleus — that ball shaped membrane containing the genome — looks very different in all three cell types, with different genes active in each. Martin Hetzer, another Salk professor, had previously identified how proteins in the nuclear membrane influence gene expression in different cancer cell types. Gage's team collaborated with Hetzer's lab to explore if similar processes operate in brain cells.
Gage's team found Nup153 to be a gatekeeper protein that induces pore formation in a nuclear membrane:
Interestingly, Nup153 levels are known to be high in cells with elevated levels of a mobile protein called Sox2. Sox2 acts as a transcription factor which floats around inside the nucleus, binding to genes, turning them on or off. By fluorescently tagging Nup153 and Sox2 in the 3 different cells types, they observed how Nup153 interacted with Sox2.
"The fact that we were able to connect transcription factors, which act as mobile switches in the pore complex — an otherwise very stable structure — offers a clue as to how cells maintain their identity through regulated gene expression," says Tomohisa Toda, a Salk research associate and first author of the paper.
Next, the team wants to explore how the interaction of the pore complex with other transcription factors affects neuronal function, which could yield insights into the underlying causes of certain neurological disorders.
• High levels of Nup153 are essential for maintaining neural progenitor cells (NeuPCs)
• Nup153 forms a complex with Sox2 in NeuPCs
• Sox2 cooperates with Nup153 to control transcriptional programs in NeuPCs
• Nup153 exerts spatially distinct bimodal gene regulation in NeuPCs
Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.
Other authors: Jonathan Y. Hsu, Sara B. Linker, Lauren Hu, Simon T. Schafer, Jerome Mertens, Felipe V. Jacinto and Martin Hetzer.
Keywords: neural progenitor cells, Nup153, Sox2, neural differentiation, nucleoporins, cell fate, key transcription factors, adult neurogenesis, spatial transcriptional regulation, bimodal gene regulation
The work was funded by: the Japan Society for the Promotion of Science, the Kanae Foundation for the Promotion of Medical Science, the Paul G. Allen Family Foundation, The JPB Foundation, The Dolby Foundation, The Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health-National Cancer Institute, the Chapman Foundation, the Waitt Foundation, and the National Institute of Neurological Disorders and Stroke Neuroscience Center.
About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
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Salk scientists find that interaction between two key proteins regulates development of neurons. A fluorescent microscopy image shows Nup153 (red) in pore complexes encircling and associating with Sox2 (green) in a precursor cell nucleus. Image Credit: Salk Institute/Waitt Center