klumpfuss distinguishes stem cells from progenitor cells during asymmetric neuroblast division

Abstract

SUMMARYAsymmetric stem cell division balances maintenance of the stem cell pool and generation of diverse cell types by simultaneously allowing one daughter progeny to maintain a stem cell fate and its sibling to acquire a progenitor cell identity. A progenitor cell possesses restricted developmental potential, and defects in the regulation of progenitor cell potential can directly impinge on the maintenance of homeostasis and contribute to tumor initiation. Despite their importance, the molecular mechanisms underlying the precise regulation of restricted developmental potential in progenitor cells remain largely unknown. We used the type II neural stem cell (neuroblast) lineage in Drosophila larval brain as a genetic model system to investigate how an intermediate neural progenitor (INP) cell acquires restricted developmental potential. We identify the transcription factor Klumpfuss (Klu) as distinguishing a type II neuroblast from an INP in larval brains. klu functions to maintain the identity of type II neuroblasts, and klu mutant larval brains show progressive loss of type II neuroblasts due to premature differentiation. Consistently, Klu protein is detected in type II neuroblasts but is undetectable in immature INPs. Misexpression of klu triggers immature INPs to revert to type II neuroblasts. In larval brains lacking brain tumor function or exhibiting constitutively activated Notch signaling, removal of klu function prevents the reversion of immature INPs. These results led us to propose that multiple mechanisms converge to exert precise control of klu and distinguish a progenitor cell from its sibling stem cell during asymmetric neuroblast division.

Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors

“…Intermediate progenitor cells possess restricted developmental potential, which allows them to give rise to exclusively differentiated progeny, thereby amplifying the output of stem cells. Accumulating evidence suggests that the acquisition of aberrant stem cell properties by intermediate progenitor cells might be an underlying mechanism that leads to the initiation of tumorigenesis (Weng et al, 2010;Liu et al, 2011;Haenfler et al, 2012;Xiao et al, 2012;Schwitalla et al, 2013;Komori et al, 2014). Thus, understanding the mechanisms that restrict the developmental potential of intermediate progenitor cells might lead to the discovery of novel strategies to attenuate tumor growth.…”

“…The type II neuroblast lineage in the fly larval brain provides an excellent genetic model in which to investigate the mechanisms that restrict the developmental potential of intermediate progenitor cells in vivo (Bello et al, 2008;Boone and Doe, 2008;Bowman et al, 2008;Weng et al, 2010;Xiao et al, 2012;Komori et al, 2014). A type II neuroblast can be unambiguously identified by the expression of Deadpan (Dpn + ) and lack of Asense (Ase -), and divides asymmetrically to self-renew and to generate a newly born immature intermediate neural progenitor (INP) (Fig.…”

“…1A). Although the expression of self-renewal factors is maintained in the type II neuroblast, their expression becomes rapidly extinguished in the newly born immature INP (Xiao et al, 2012). This newly born INP undergoes a stereotypical maturation process during which its developmental potential becomes stably restricted and the expression of Ase is activated.…”

“…The neuroblast self-renewal factors include Dpn, Klumpfuss (Klu), Enhancer of split mγ [E(spl)mγ] and Notch (Weng et al, 2010;San-Juán and Baonza, 2011;Xiao et al, 2012;Zacharioudaki et al, 2012;Zhu et al, 2012). Removal of Notch function alone or dpn and E(spl)mγ function simultaneously leads to premature neuroblast differentiation, whereas overexpression of any of the neuroblast self-renewal factors in type II neuroblasts leads to massive formation of supernumerary neuroblasts.…”

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

“…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).…”