Neural stem cell-encoded temporal patterning delineates an early window of malignant susceptibility in Drosophila.
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.
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Karine
K
Narbonne-Reveau
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Elodie
E
Lanet
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Caroline
C
Dillard
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Sophie
S
Foppolo
Department of Biology, Indiana University, Bloomington, United States.
Ching-Huan
CH
Chen
MGX-Montpellier GenomiX, Institut de Génomique Fonctionnelle, Montpellier, France.
Hugues
H
Parrinello
MGX-Montpellier GenomiX, Institut de Génomique Fonctionnelle, Montpellier, France.
Stéphanie
S
Rialle
Department of Biology, Indiana University, Bloomington, United States.
Nicholas S
NS
Sokol
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Cédric
0000-0001-8931-1419
C
Maurange
D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004198:Disease Susceptibility; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D058953:Neural Stem Cells / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D013997:Time Factors
C515167:Chinmo protein, Drosophila; D029721:Drosophila Proteins; C498778:Imp protein, Drosophila; C000605000:Lin-28 protein, Drosophila; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins
D. melanogaster; cancer biology; developmental biology; developmental origin of cancer; neural stem cell; neuroblasts; pediatric cancer; stem cells