Temporal and spatial regulation of neural stem cells

NAISS 2023/22-515


NAISS Small Compute

Principal Investigator:

Qi Dai


Stockholms universitet

Start Date:


End Date:


Primary Classification:

10604: Cell Biology



A limited number of neural stem cells (NSCs) in the developing mammalian brain give rise to millions of neurons and supporting cell types. The mechanisms that control NSC proliferation and specification remain to be explored. This project aims to obtain a deeper understanding of NSC regulation using the developing mouse brain as a model, with an ultimate goal of gaining mechanistic insights into human brain development and etiology of neurological diseases. In particular, we focus on two brain regions. One is the developing cortex where we examine how NSC cell fate is regulated by Notch signalling. We found that the level of Notch activity is not uniform in the same pool of NSCs and that differential expression levels of the ligands and receptors cannot simply explain cell fate choices. These observations challenge the classic view of how Notch functions in NSCs. We hypothesize that NSCs and their daughter cells have heterogenous Notch activity and such heterogeneity allows cell fate maintenance and transition to occur at the same time. In the second brain region, we study how quantitative levels of BMP and Wnt signalling determine neural versus non-neural epithelial cell fate and stem cell proliferative versus quiescent states. We hypothesize that the relative strength of Wnt and BMP signalling determines the gene regulatory network that favour proliferative over quiescent stem cell state and that the transcription factor, PRDM16, is a key mediator that buffer the relative strength of these two signalling pathways. Cell signaling pathways are evolutionarily conserved and fundamental regulators in animal development. Despite extensive studies and much progress in understanding the function of these regulators, many questions remain. For example, as these signalling molecules are utilized “everywhere” and by “everything”, how is the specificity of the signalling output achieved to fulfil context-dependent need? Addressing these questions is not only crucial for fully understanding the basic principles of signalling operation in normal development and homeostasis but also for tackling disease mechanisms associated with these factors. Moreover, the balance of stem cell proliferation and quiescence underlies the capacity of tissue regeneration, and disrupting such balance can lead to premature tissue degeneration or the opposite outcome, tumour formation. We expect that the mechanisms that regulate stem cell behaviors in normal conditions are used by tumor cells during tissue overgrowth.