Brain stem cells: Progenitors knocked down a Notch
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Intermediate progenitor cells in the brain employ a non-canonical Notch signaling pathway to arrest their differentiation into neurons.
Neurons and glial cells in the brain originate as intermediate neural progenitors (INPs) and neural stem cells (NSCs). While it is known that Notch-dependent target gene activation antagonizes neuronal differentiation and maintains the stem cell status of NSCs, the role of Notch signaling in the inhibition of INP differentiation into neurons has remained elusive. In many cell types, including NSCs, it has been shown that the activation of target genes via Notch signaling involves the cooperation between the proteolytically cleaved intracellular domain of the Notch receptor (NICD) and the transcriptional regulator C-promoter binding factor 1 (CBF1). Mizutani et al. now report in Nature that it is the involvement of CBF1 that distinguishes NSCs from INPs.
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The authors generated transgenic mice with a CBF1 responsive element that regulates the expression of enhanced green fluorescent protein (EGFP) to measure Notch signaling activity. In the ventricular zone of the developing mouse brain, Notch-responding cell clusters expressed either high or low amounts of EGFP. The authors found that EGFPhigh cells in vivo drove expression from the GLAST (glutamate–aspartate transporter) promoter — indicative of NSC character — while the EGFPlow cells drove expression from the Tα1 (α1 tubulin) promoter, which is indicative of INP character. The authors prospectively separated these cell types using flow cytometry, and confirmed their NSC or INP character via in vitro differentiation and in vivo transplantation assays.
Knockdown of CBF1 activity in vivo converted NSCs into INPs. However, expression of an activated form of CBF1 (linked to the viral transactivator VP16) inhibited this conversion, suggesting that the responsiveness of INPs to CBF1 is lost after their differentiation from NSCs. NICD1 over-expression inhibited the differentiation of INPs into neurons even after the conversion of NSCs to INPs by CBF1 knockdown. This gives further support to a CBF1-independent role for Notch signaling in INPs and suggests that Notch signaling arrests differentiation of both INPs and NSCs. However, while the Notch pathway utilizes CBF1 in NSCs to prevent their differentiation into INPs, the pathway also acts independently of CBF1 to prevent the further differentiation of INPs into neurons.
It has been suggested that Notch signaling also diverges in response to CBF1 activation in hematopoietic stem and progenitor cells. Thus, the way in which signaling downstream of Notch receptor activation is regulated might be a more general way to distinguish between stem cells and progenitor cells.
Mirko von Elstermann
Functional Glycomics Gateway
Reference
- Mizutani K. et al. Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 449, 351-355 (2007) | Article | PubMed |
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