Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression

Abstract

SUMMARYDuring neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers.

sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system

“…These regulators exert their roles by regulating the key cell cycle genes (Baumgardt et al, 2014). In addition, the canonical Notch pathway was also found to be important for the type I>0 switch, via regulation of all four key cell cycle genes (Ulvklo et al, 2012;Bivik et al, 2015Bivik et al, , 2016. Notch signaling is initially off in NBs -a prerequisite for establishment of NB cell identity in the neuroectoderm -but is gradually activated during lineage progression (Ulvklo et al, 2012;Bivik et al, 2016).…”

“…These three basic proliferation modes have been described in many animal species, and in Drosophila they are referred to as type 0, type I and type II, respectively (Bello et al, 2008;Boone and Doe, 2008;Bowman et al, 2008;Baumgardt et al, 2014;Bertet et al, 2014). The control of alternate daughter proliferation is of profound importance because it can act to expand the number of neurons/glia generated at a certain temporal stage in a developing lineage (Ulvklo et al, 2012). It may furthermore act to control overall cell number in different regions of the developing nervous system, and might even act to modify its basic structure (Kriegstein et al, 2006;Fish et al, 2008;Nonaka-Kinoshita et al, 2013).…”

Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS

“…Furthermore, as mentioned, previous studies have suggested links between Paf1C and Notch target genes e.g., the HES genes [235,236], and we know that Notch is critical for NB division type I>0 switch [167,254]. Hence, we tested the level of E(spl)-HLHm8 i.e., a core player in Notch signaling of developing CNS [167], to detect a putative relation between Ctr9 and Notch.…”

“…This was identified in the lineages NB5-6T, NB3-3A and NB7-3A, and is critical for correct lineage progression and consequentially VNC development [71,110,[165][166][167]. All of these three types of division modes have also been observed in the developing mammalian brain [161], which suggests that fundamental molecular aspects of alternate daughter proliferation have been conserved throughout evolution [5,168].…”

“…Hence, we tested the level of E(spl)-HLHm8 i.e., a core player in Notch signaling of developing CNS [167], to detect a putative relation between Ctr9 and Notch. Although Ctr9 mutants showed no effect on E(spl)-HLHm8-GFP, our transcription analysis revealed six of the other Notch target genes [255] to be effected in the Ctr9 mutants: E(spl)m6, E(spl)m5-HLH, E(spl)m4, Him, peb and stg.…”