Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Regulated mRNA stability and translation in neural stem cell development

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £2.0M
Period Feb 2018 — Feb 2023

In plain English

AI plain-English summary

Neural stem cells sometimes make proteins without first making the corresponding messenger RNAs, a discovery that overturns the textbook view of how cells control protein production. The human brain contains billions of diverse cells, all arising from a small pool of neural stem cells. Biologists have long assumed that the amount of a protein in a cell is set by how often its gene is transcribed into RNA. This team has found clear exceptions: key regulators of stem cell behaviour, including the proteins Pros and Myc, show no correlation between their RNA and protein levels. The researchers have identified 21 additional examples, all controlled by the same RNA-binding proteins, Syp and Imp, which bind to unusually long stretches of non-coding RNA. This project will map the full set of RNA stability signals across the genome and work out exactly how these binding proteins control when and where proteins are made. This is fundamental science. It reveals a hidden layer of regulation that operates alongside transcription in complex tissues. If successful, it will rewrite the basic understanding of how the brain develops. That deeper knowledge could eventually help explain why neural development sometimes goes wrong in disease, but the immediate payoff is a corrected model of how cells actually work.

View original technical description
Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

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Researchers

Ilan Davis (EPMC Awardee)

Related Research

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Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.