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.
Highlights
Stem cells are defined by their ability to self-renew and produce differentiating daughter cells
Da acts as a tumor suppressor in optic lobe neuroblasts To further characterize the overproliferation caused by da
Da was expressed in all NBs of the central brain and in some progenitor cells (Figures S2A–S2B’’’) we did not find any phenotype in these lineages when we induced da3 amorphic mutant clones using mosaic analysis with a repressible cell marker (MARCM) technique [37] (0%, n = 19 for type I NB lineages, and 0%, n = 16 for type II NB lineages) (Figures S2C–S2F’’)
Summary
Stem cells are defined by their ability to self-renew and produce differentiating daughter cells. In the larval brain several types of NBs are defined by their locations and ways of cell division [3]. Type I NBs divide asymmetrically and produce another NB and a ganglion mother cell (GMC), which divides symmetrically into two neurons and/ or glia cells. While NBs in the central brain are formed during the embryonic stage, NBs in the so-called optic lobes show a different mode of neurogenssis. There are two proliferating centers in the optic lobe, the outer and inner proliferation center. In both areas, the number of NBs increases during larval stages. Medulla NBs divide asymmetrically and display a lineage similar to the type I NBs in the central brain
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