TY - JOUR
T1 - Repression of differentiation genes by Hes transcription factors fuels neural tumour growth in Drosophila
AU - Voutyraki, Chrysanthi
AU - Choromidis, Alexandros
AU - Theodorou, Vasiliki
AU - Efraimoglou, Christina
AU - Anagnostopoulos, Gerasimos
AU - Magadi, Srivathsa S.
AU - Grammenoudi, Sofia
AU - Zacharioudaki, Evanthia
AU - Delidakis, Christos
N1 - Publisher Copyright:
© 2021 UPV/EHU Press.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Background: Neural stem cells (NSC) in divide asymmetrically to generate one cell that retains stem cell identity and another that is routed to differentiation. Prolonged mitotic activity of the NSCs gives rise to the plethora of neurons and glial cells that wire the brain and nerve cord. Genetic insults, such as excess of Notch signaling, perturb the normal NSC proliferation programs and trigger the formation of NSC hyperplasias, which can subsequently progress to malignancies. Hes proteins are crucial mediators of Notch signaling, and in the NSC context they act by repressing a cohort of early pro-differentiation transcription factors. Downregulation of these pro-differentiation factors makes NSC progeny cells susceptible to adopting an aberrant stem cell program. We have recently shown that Hes overexpression in Drosophila leads to NSC hyperplasias that progress to malignant tumours after allografting to adult hosts. Methods: We have combined genetic analysis, tissue allografting and transcriptomic approaches to address the role of Hes genes in NSC malignant transformation. Results: We show that the E (spl) genes are important mediators in the progression of Notch hyperplasias to malignancy, since allografts lacking the E (spl) genes grow much more slowly. We further present RNA profiling of Hes-induced tumours at two different stages after allografting. We find that the same cohort of differentiation-promoting transcription factors that are repressed in the primary hyperplasias continue to be downregulated after transplantation. This is accompanied by an upregulation of stress-response genes and metabolic reprogramming. Conclusions: The combination of dedifferentiation and cell physiology changes most likely drive tumour growth.
AB - Background: Neural stem cells (NSC) in divide asymmetrically to generate one cell that retains stem cell identity and another that is routed to differentiation. Prolonged mitotic activity of the NSCs gives rise to the plethora of neurons and glial cells that wire the brain and nerve cord. Genetic insults, such as excess of Notch signaling, perturb the normal NSC proliferation programs and trigger the formation of NSC hyperplasias, which can subsequently progress to malignancies. Hes proteins are crucial mediators of Notch signaling, and in the NSC context they act by repressing a cohort of early pro-differentiation transcription factors. Downregulation of these pro-differentiation factors makes NSC progeny cells susceptible to adopting an aberrant stem cell program. We have recently shown that Hes overexpression in Drosophila leads to NSC hyperplasias that progress to malignant tumours after allografting to adult hosts. Methods: We have combined genetic analysis, tissue allografting and transcriptomic approaches to address the role of Hes genes in NSC malignant transformation. Results: We show that the E (spl) genes are important mediators in the progression of Notch hyperplasias to malignancy, since allografts lacking the E (spl) genes grow much more slowly. We further present RNA profiling of Hes-induced tumours at two different stages after allografting. We find that the same cohort of differentiation-promoting transcription factors that are repressed in the primary hyperplasias continue to be downregulated after transplantation. This is accompanied by an upregulation of stress-response genes and metabolic reprogramming. Conclusions: The combination of dedifferentiation and cell physiology changes most likely drive tumour growth.
KW - CNS tumour
KW - Drosophila
KW - Hes proteins
KW - neural stem cells
KW - Notch
UR - http://www.scopus.com/inward/record.url?scp=85130642050&partnerID=8YFLogxK
U2 - 10.1387/ijdb.210187cd
DO - 10.1387/ijdb.210187cd
M3 - Article
C2 - 34881794
AN - SCOPUS:85130642050
SN - 0214-6282
VL - 66
SP - 211
EP - 222
JO - International Journal of Developmental Biology
JF - International Journal of Developmental Biology
IS - 1-3
ER -