Neural stem cell-encoded temporal patterning delineates an early window of malignant susceptibility in Drosophila

Abstract

Pediatric neural tumors are often initiated during early development and can undergo very rapid transformation. However, the molecular basis of this early malignant susceptibility remains unknown. During Drosophila development, neural stem cells (NSCs) divide asymmetrically and generate intermediate progenitors that rapidly differentiate in neurons. Upon gene inactivation, these progeny can dedifferentiate and generate malignant tumors. Here, we find that intermediate progenitors are prone to malignancy only when born during an early window of development while expressing the transcription factor Chinmo, and the mRNA-binding proteins Imp/IGF2BP and Lin-28. These genes compose an oncogenic module that is coopted upon dedifferentiation of early-born intermediate progenitors to drive unlimited tumor growth. In late larvae, temporal transcription factor progression in NSCs silences the module, thereby limiting mitotic potential and terminating the window of malignant susceptibility. Thus, this study identifies the gene regulatory network that confers malignant potential to neural tumors with early developmental origins.DOI: http://dx.doi.org/10.7554/eLife.13463.001

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

“…Cooperation between LIN28 and dIMP has recently been highlighted in neuroblast (NB)-derived tumors in Drosophila melanogaster (Narbonne-Reveau et al 2016). Together with the transcription factor Chinmo, dIMP and LIN28 form the core of an early oncogenic module that controls Drosophila NB (dNB) mitotic activity and that can be co-opted by susceptible cells to initiate malignant growth during early larval development.…”

“…Whether this subpopulation of cells represents CSCs or a transient amplifying population of progenitors derived from a distinct set of CSCs remains to be determined. The model, however, may be relevant to highly aggressive pediatric neural tumors that are often initiated during early development (Narbonne-Reveau et al 2016). …”

Playing Well with Others: Extrinsic Cues Regulate Neural Progenitor Temporal Identity to Generate Neuronal Diversity

“…In contrast, larval neuroblasts can divide >50 times over 120h to generate hundreds of neurons and glia [47] -- this likely requires a completely different temporal patterning mechanism, particularly to coordinate the timing of neuron production between different lineages, which might be important for neural circuit assembly. Indeed, work over the past decade has identified several genes with broad expression domains in early-born or late-born neurons [48-50], but few candidate TTFs expressed for just one or two cell divisions [51], as in the embryonic TTF cascade. For example, the Chinmo transcription factor, Lin-28 transcription factor, and Imp RNA-binding protein are expressed in all early-born neurons (0-60h after larval hatching, ALH), whereas the Broad transcription factor and Syncrip RNA-binding protein are expressed in all late-born neurons (60-120h ALH) [48-50].…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…Importantly, older neuroblasts during the second half of larval life are still proliferating but have little or no response to the same oncogenic mutations. 24 The normal function of Chinmo, Lin-28 and Imp is to specify early-born larval neurons and glia, 25,26 but they also open a competence window for "single hit" tumor formation; it is unknown if these two functions are related. This suite of proteins is unlikely to act on a single locus or a highly specific process because they provide tumor-forming competence to a diverse array of oncogenic mutations, including mutants in two different transcription factors (Prospero and Nerfin-1) and an RNA-binding protein (Brain tumor).…”

“…24,25,26,27,28 Recent work has shown that this suite of factors gives neuroblasts competence to form malignant tumors in response to several oncogenic mutations, including mutants in transcription factors (Prospero, Nerfin-1), and an RNA-binding protein (Brain tumor; Brat). Importantly, older neuroblasts during the second half of larval life are still proliferating but have little or no response to the same oncogenic mutations.…”