Science for Health
21 August 2013
Scientists at NIMR have developed a new cell culture system and used it to demonstrate a key role for the Nfix gene in regulating neural stem cell quiescence. The research is published in Genes and Development.
The majority of neural stem cells (NSCs) in the adult brain are in a dormant state called quiescence where they cannot produce new cells. Quiescence safeguards the regenerative potential of stem cell populations by preventing their premature exhaustion. Little is known of the cellular factors that control NSC quiescence, because NSCs are few in number and difficult to study in the brain in situ and also due to the lack of a cell culture model.
Ben Martynoga (pictured) and colleagues in Francois Guillemot's lab in NIMR’s Division of Molecular Neurobiology plus collaborators have developed and validated a new cell culture system where NSCs can be efficiently driven in and out of quiescence. They used epigenomic profiling to identify gene control regions, called enhancers, that are active in either quiescent or proliferating NSCs. Using genome-wide location analysis and overexpression and silencing experiments they showed that the transcription factor Nfix binds to a huge fraction of NSC enhancers specific for the quiescent state and regulates many genes involved in quiescence. Their functional experiments show that Nfix is necessary and sufficient for quiescence in cultured NSCs. They then use mice mutant for Nfix to show that this factor is also required for maintenance of quiescence in the postnatal mouse hippocampus in vivo.
Our study illustrates how modeling stem cell physiology in culture can be used in combination with epigenomic profiling to identify key transcription factors regulating stem cell states. We have established a platform to understand how the signaling environment of the niche influences NSC physiology and to decipher the regulatory networks that control the different NSC states. Since the balance between NSC quiescence and activation is implicated in cancer onset and affected by diverse physiological and pathological inputs including ageing, mental illness and cognitive stimulation, the identification of Nfix as a new and important transcriptional regulator of this process might have therapeutic potential.
Ben Martynoga, Juan L. Mateo, Bo Zhou, Jimena Andersen, Angeliki Achimastou, Noelia Urbán, Debbie van den Berg, Dimitra Georgopoulou, Suzana Hadjur, Joachim Wittbrodt, Laurence Ettwiller, Michael Piper, Richard M. Gronostajski, and François Guillemot (2013)
Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence
Genes and Development 27:1769-86. Free full text.
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