Abstract
ABSTRACTThe transcriptional mechanisms that allow neural stem cells (NSC) to balance self-renewal with differentiation are not well understood. Employing an in vivo RNAi screen we identify here NSC-TAFs, a subset of nine TATA-binding protein associated factors (TAFs), as NSC identity genes in Drosophila. We found that depletion of NSC-TAFs results in decreased NSC clone size, reduced proliferation, defective cell polarity and increased hypersensitivity to cell cycle perturbation, without affecting NSC survival. Integrated gene expression and genomic binding analyses revealed that NSC-TAFs function with both TBP and TRF2, and that NSC-TAF-TBP and NSC-TAF-TRF2 shared target genes encode different subsets of transcription factors and RNA-binding proteins with established or emerging roles in NSC identity and brain development. Taken together, our results demonstrate that core promoter factors are selectively required for NSC identity in vivo by promoting cell cycle progression and NSC cell polarity. Because pathogenic variants in a subset of TAFs have all been linked to human neurological disorders, this work may stimulate and inform future animal models of TAF-linked neurological disorders.
Highlights
Brains from a wide range of animal species are populated by Neural Stem Cells (NSCs)
By combining genetics and low-input genomics, we show that TATA-binding protein associated factors (TAFs) directly control NSC cell division and cell polarity but do not appear to be required for NSC survival
We further show that TAFs accomplish these functions by associating either with their canonical partner TATA box-binding protein (TBP) (TATA-binding protein) or the related protein TBP-related factor 2 (TRF2)
Summary
Brains from a wide range of animal species are populated by Neural Stem Cells (NSCs). Type I NSCs express two related bHLH transcription factors, Asense (Ase) and Deadpan (Dpn), and divide asymmetrically into a single type I NSC and into a differentiating daughter, the ganglion mother cell (GMC). Type II NSCs express Dpn but not Ase, and divide into another type II NSC and an Intermediate Neuronal Progenitor (INP). The INP expresses Ase and undergoes limited rounds of self-renewing divisions while generating GMCs, much like a type I NSC (Fig 1A). Asymmetric distribution of cell fate determinants such as the transcription factor Prospero and the RNA-binding protein Brat is thought to control differentiation in type I and type II lineages respectively [5,6,7,8]. We define NSC identity as the suite of stem cell attributes such as asymmetric cell division, self-renewal, survival, growth and proliferation that collectively distinguish NSCs from their differentiating and differentiated progeny
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