Aging Neural Progenitors Lose Competence to Respond to Mitogenic Notch Signaling

Abstract

Drosophila neural stem cells (neuroblasts) are a powerful model system for investigating stem cell self-renewal, specification of temporal identity, and progressive restriction in competence. Notch signaling is a conserved cue that is an important determinant of cell fate in many contexts across animal development; for example mammalian T cell differentiation in the thymus and neuroblast specification in Drosophila are both regulated by Notch signaling. However, Notch also functions as a mitogen, and constitutive Notch signaling potentiates T cell leukemia as well as Drosophila neuroblast tumors. While the role of Notch signaling has been studied in these and other cell types, it remains unclear how stem cells and progenitors change competence to respond to Notch over time. Notch is required in type II neuroblasts for normal development of their transit amplifying progeny, intermediate neural progenitors (INPs). Here we find that aging INPs lose competence to respond to constitutively active Notch signaling. Moreover, we show that reducing the levels of the old INP temporal transcription factor Eyeless/Pax6 allows Notch signaling to promote the de-differentiation of INP progeny into ectopic INPs, thereby creating a proliferative mass of ectopic progenitors in the brain. These findings provide a new system for studying progenitor competence, and identify a novel role for the conserved transcription factor Eyeless/Pax6 in blocking Notch signaling during development.

Notch maintains Drosophila type II neuroblasts by suppressing the expression of the Fez transcription factor Earmuff

“…Numb inhibits Notch signaling in immature INPs (imINPs), whereas Brat reduces the activity of Armadillo (Arm; β-catenin) in imINPs (Bowman et al, 2008;Komori et al, 2014b). Erm functions together with the SWI/SNF chromatin-remodeling complex in imINPs to restrict the developmental potential of INPs (Eroglu et al, 2014;Farnsworth et al, 2015;Janssens et al, 2014;Koe et al, 2014). Meanwhile, INPs need to avoid differentiating into GMCs prematurely and exiting the cell cycle.…”

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

“…2h). In contrast, we found that NICD expression in old EyelessC INPs had no effect on the fate or proliferation of INPs, even when the exact same promoter was used to drive expression to ensure equal levels of Notch activity 39 (Fig. 2i).…”

“…Many stem cells and progenitors require Notch signaling to maintain proliferation, so we asked whether Eyeless limits Notch signaling in aging INPs. It is well known that misexpression of the Notch intracellular domain (NICD), a potent inducer of Notch target gene expression, 38 in Type II NBs and young Eyeless-negative INPs results in tumor formation 15,39,40,41,42 ( Fig. 2h).…”

“…Thus, aging INPs lose competence to respond to Notch signaling, and Eyeless is required to block Notch-induced proliferation in old INP progeny. 39 How does Ey block Notch signaling? An attractive model is that Ey recruits SWI/SNF proteins to prevent activation of Notch target genes in GMCs.…”

Transgenic mouse models for studying adult neurogenesis

“…Notch signaling is an evolutionarily conserved pathway (Andersson et al, 2011) that plays a key role in development, through diverse effects on survival, differentiation and proliferation (Alunni et al, 2013; Breunig et al, 2007; Giachino and Taylor, 2014), that depend on signal strength (Chapouton et al, 2010; Gama-Norton et al, 2015; Ninov et al, 2012; Shimojo et al, 2008) and cellular context (Basak et al, 2012; Farnsworth et al, 2015; Lugert et al, 2010). Hairy and enhancer of split (Hes) genes are downstream targets of Notch pathway.…”