title: A regulatory transcriptional loop controls proliferation and differentiation in Drosophila neural stem cells.
abstract: Neurogenesis is initiated by a set of basic Helix-Loop-Helix (bHLH) transcription factors that specify neural progenitors and allow them to generate neurons in multiple rounds of asymmetric cell division. The Drosophila Daughterless (Da) protein and its mammalian counterparts (E12/E47) act as heterodimerization factors for proneural genes and are therefore critically required for neurogenesis. Here, we demonstrate that Da can also be an inhibitor of the neural progenitor fate whose absence leads to stem cell overproliferation and tumor formation. We explain this paradox by demonstrating that Da induces the differentiation factor Prospero (Pros) whose asymmetric segregation is essential for differentiation in one of the two daughter cells. Da co-operates with the bHLH transcription factor Asense, whereas the other proneural genes are dispensible. After mitosis, Pros terminates Asense expression in one of the two daughter cells. In da mutants, pros is not expressed, leading to the formation of lethal transplantable brain tumors. Our results define a transcriptional feedback loop that regulates the balance between self-renewal and differentiation in Drosophila optic lobe neuroblasts. They indicate that initiation of a neural differentiation program in stem cells is essential to prevent tumorigenesis.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yasugi
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Reichert
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Knoblich
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008938:Mitosis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C090080:Da protein, Drosophila; C407353:ase protein, Drosophila; C073099:pros protein, Drosophila