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04.12.2017

Brat levels direct the maturation of neural stem cells

The RNA binding protein Brain tumor (Brat) acts as a tumor suppressor in the brain of the fruit fly Drosophila, but how it prevents tumorigenesis has been unclear. The Knoblich lab has discovered that Brat controls cell fate in neural stem cell lineages via differential repression of the transcription factors Deadpan and Zelda.

The image represents a GFP-labeled Type-II Neuroblast Lineage, where different stages of INPs maturation can be visualized by the sequential appearance of Asense (blue) and Deadpan (red).

Each of our organs is maintained by a pool of undifferentiated stem cells. Stem cells have the ability to divide asymmetrically: one daughter self-renews and sustains the undifferentiated pool, while the other daughter differentiates and acquires a new fate and function. Dysregulation of the balance between self-renewal and differentiation can trigger stem cell overgrowth and cancer.

Brat is expressed in Drosophila larvae neural stem cells, called neuroblasts, and loss of Brat leads to brain tumors. The Knoblich lab has now discovered that Brat suppresses tumor formation in part by repressing the transcription factor Zelda in neural progenitors. Unlike normal flies, intermediate neural progenitors (INPs) in brat mutants fail to repress Zelda and Deadpan, a previously known Brat target. Brat mutant INPs become tumor-initiating cells rather than committed mature INPs. Inhibition of either transcription factor prevents the tumorigenesis induced by loss of Brat.

Knoblich’s group found that Zelda is expressed in the neuroblasts of healthy flies, and is required for Deadpan expression later during INP maturation. In the absence of Zelda, reduced Deadpan levels lead to underproliferation of INPs.

During normal differentiation, Brat becomes enriched in immature INPs and binds to Zelda and Deadpan mRNAs, mediating their degradation. Interestingly, Brat binds Deadpan mRNA with lower affinity than Zelda mRNA, and higher levels of Brat are required to repress Deadpan compared to Zelda in INPs. Indeed, Brat levels decrease during INP maturation, which correlates with de-repression specifically of Deadpan. Therefore, Brat levels appear to regulate the stepwise post-transcriptional inhibition of Zelda and Deadpan. This results in the sequential generation of cell fates during neuroblast differentiation.

Brat belongs to a conserved family of proteins that are known to influence cell fate determination. In humans, the Brat homologue TRIM3 acts as a tumor suppressor in glioblastoma by promoting differentiation and suppressing c-Myc. Whether TRIM3 inhibits c-Myc via a similar mechanism as Brat is unknown.

Transit-amplifying lineages, like the INPs in flies, are found in human brain development. Differential regulation of transcriptional activators like Zelda might control cell fate specification in human neural stem cell lineages.

Original publication: Reichardt, I.; Bonnay, F.; et.al. The Tumor suppressor Brat controls neuronal stem cell lineages by inhibiting Deadpan and Zelda. EMBO reports (2017) e201744188
DOI: https://doi.org/10.15252/embr.201744188