The tumor suppressor Brat controls neuronal stem cell lineages by inhibiting Deadpan and Zelda. (30th November 2017)

• Record Type: Journal Article
• Authors: Reichardt, Ilka; Bonnay, François; Steinmann, Victoria; Loedige, Inga; Burkard, Thomas R; Meister, Gunter; Knoblich, Juergen A
• Is Part Of: EMBO reports. Volume 19:Number 1(2018)
• Page Start: 102
• Page End: 117
• Publication Date: 2017-11-30
• Subjects: neurogenesis -- stem cells -- tumorigenesis -- RNA‐binding protein; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201744188
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The TRIM‐NHL protein Brain tumor (Brat) acts as a tumor suppressor in the Drosophila brain, but how it suppresses tumor formation is not completely understood. Here, we combine temperature‐controlled brat RNAi with transcriptome analysis to identify the immediate Brat targets in Drosophila neuroblasts. Besides the known target Deadpan (Dpn), our experiments identify the transcription factor Zelda (Zld) as a critical target of Brat. Our data show that Zld is expressed in neuroblasts and required to allow re‐expression of Dpn in transit‐amplifying intermediate neural progenitors. Upon neuroblast division, Brat is enriched in one daughter cell where its NHL domain directly binds to specific motifs in the 3′UTR of dpn and zld mRNA to mediate their degradation. In brat mutants, both Dpn and Zld continue to be expressed, but inhibition of either transcription factor prevents tumorigenesis. Our genetic and biochemical data indicate that Dpn inhibition requires higher Brat levels than Zld inhibition and suggest a model where stepwise post‐transcriptional inhibition of distinct factors ensures sequential generation of fates in a stem cell lineage. Synopsis: Brat controls lineage progression in neural stem cells via coordinated post‐transcriptional suppression of Deadpan (Dpn) and Zelda (Zld). While even low concentrations of Brat can suppress zld, dpn repression requires higher Brat concentrations only achieved in immature intermediate neural progenitors. The transcription factor Zelda is a critical target of the RNA binding protein Brat. Zelda is required for correct proliferation of intermediate neural progenitors in type II neuroblast lineages. Brat acts on its RNA targets deadpan and zelda with distinct affinities to ensure proper neural stem cell lineage progression. Abstract : Brat controls lineage progression in neural stem cells via coordinated post‐transcriptional suppression of Deadpan (Dpn) and Zelda (Zld). While even low concentrations of Brat can suppress zld, dpn repression requires higher Brat concentrations only achieved in immature intermediate neural progenitors.