​STARGAZING: How are astrocytes made?
Niharika Singh, 2nd year PhD, Cardiff University
BACKGROUND:
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As a final year undergraduate pursuing a Zoology (Honours) degree from the University of Calcutta, I was fascinated by Neuroscience when I first learnt of adult neurogenesis. The generation of neurons in the adult brain as opposed to the existing paradigm of restricted neurogenesis during an embryo's development appeared to me an area of unending prospects once tapped and understood completely. My interests were rooted in studying patient histories focusing on hippocampal degeneration and it was then that I stumbled upon the story of an amnestic patient, Clive Wearing. In the documentary of his life, Clive kept apologizing for his anterograde amnesia, which prevented him from retaining information beyond seven seconds. It unsettled me to watch Clive apologizing for something beyond his control when in reality the power to make a difference lies with us- the scientific community. Clive’s story became the driving force nurturing my interest in hippocampal adult neurogenesis and moulded my decision to pursue a Masters in Neuroscience at the School of Studies in Neuroscience, Gwalior, funded by the Department of Biotechnology, Ministry of Science and Technology, Government of India. My M.Sc. dissertation project was conducted at the Indian Institute of Technology, Madras, where I used computational neuroscience to model the exploratory dynamics in the STN-GPe subsystem of the basal ganglia. Currently, I am pursuing a PhD in Neuroscience whereby I will investigate the transcriptional regulation of astrocyte specification across development and adult neurogenesis, furthering our understanding of the fate specification of neural stem cells during adult neurogenesis.
Astrocytes-our star-shaped glial cells are the most abundant cell type in the brain where they perform a multitude of crucial functions for instance providing structural support for neurons, maintaining the suitable chemical environment for neural signalling, and in the formation and maintenance of the brain circuitry. They have also been implicated as central players in several disorders of which glioblastoma is the most aggressive and lethal. This is where my second point of interest walks in. Zeb1 is a transcription factor which has been extensively studied for its role in maintaining the stemness of neural progenitor population and facilitating epithelial-mesenchymal transition thereby leading to metastasis in cancers.
Fascinatingly, when Zeb1 was deleted from the hippocampal progenitors, it led to an increase in the number of neurons at the expense of glial cells. This suggested a role for Zeb1 beyond stem cell maintenance in determining the type of cells produced by neural precursors. Interestingly, adult astrocytes also express Zeb1.
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METHODOLOGY:
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This critical observation tunnelled to further important questions trying to disseminate the precise role of Zeb1 in frame of astrocyte generation. And this is where my project steps in. Using computational bioinformatics, developmental neuroscience, and stem cell biology, I ask 3 questions:
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1. What is the role of Zeb1 during embryonic glial development?
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2. What are the gene networks involved in this regulation?
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3. What role does Zeb1 play in mature astrocytes?
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RESULTS and FUTURE WORK:
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As part of my rotation project, I was able to show that even though Zeb1 is expressed globally in all mature astrocytes, it has very region-specific effects that are translated in its morphology. We observed highly significant immune-related signatures in the striatum and hippocampus compared with other brain regions. These differences were also translated in the morphology of the astrocytes which is interesting because unlike neurons, astrocytes are not excitable cells, and it is the morphology of these glial cells that allows us to peak into the pathophysiology. I will be following this up with detailed morphometric analysis (surface rendering and filament tracing) to gain a more quantifiable understanding. On the animal front, I will be performing in-utero electroporation surgeries to deliver Cre to the brains of the developing embryos to delete Zeb1 and study its implications on gliogenesis during developmental neurogenesis.
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FUNDED BY:
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CONTACT:
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Niharika Singh