# Multi-layered Control of the Exit from Stemness

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $330,295

## Abstract

The mechanisms promoting the exit from stemness in normal neural stem cells likely can also drive brain
tumor stem cells to differentiate. Thus, insights into control of the exit from stemness will improve our
understanding of normal neurogenesis as well as brain tumor development. To exit from stemness, neural
stem cell progeny must synchronously terminate self-renewal gene activity at the level of mRNAs and proteins.
While tremandous progress has been made toward understanding the termination of self-renewal gene
transcription during the exit from stemness, little is known about how post-transcriptional regulatory
mechanisms terminate self-renewal gene activity. Importantly, nothing is known about how distinct control
layers function synergistically to terminate self-renewal gene activity at all levels. By using the fly type II neural
stem cell lineage as a paradigm, we demonstrated that transcriptional, translational and post-translational
control function as part of an integrated gene regulation system that synchronously terminates self-renewal
gene activity at all levels in the stem cell progeny. In this proposal, we focus on translational and post-
translational control of self-renewal gene activity. We showed that RNA-binding protein complexes that are
active in the stem cell progeny expedite self-renewal gene transcripts for decay by binding unique sequences
in their 3'UTRs and recruiting multiple deadenylase concurrently. In addition, we showed that the combined
effect of protein sequestration and proteolysis directed by multiple ubiquitin E3 ligase complexes rapidly and
robustly terminates self-renewal protein activity. A robust transition from an “ON” to an “OFF” state is also
required for precise spatiotemporal activity of many developmental signaling mechanisms that control
patterning, proliferation and cell fate specification. Insights into our proposed integrated gene regulation system
will be broadly applicable to the control of the exit from stemness in all stem cell lineages as well as the
regulation of numerous cell fate decisions during normal development.

## Key facts

- **NIH application ID:** 10113683
- **Project number:** 5R01NS107496-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Cheng-Yu Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,295
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113683

## Citation

> US National Institutes of Health, RePORTER application 10113683, Multi-layered Control of the Exit from Stemness (5R01NS107496-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10113683. Licensed CC0.

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