Neural Lineage Progression Controlled by a Temporal Proliferation Program

Abstract

Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.

DrosophilaNeuroblast Selection Gated by Notch, Snail, SoxB and EMT Gene Interplay

“…While, sna, esg, wor triple mutants do not show an apparent reduction in early NB numbers (Ashraf et al, 1999), wor mutants, also heterozygous for sna and esg, display a loss of NBs at later stages (Bahrampour et al, 2017). In addition, co-misexpression of a set of NB factors, which included Wor and SoxN, was shown to be sufficient for generating ectopic NBs broadly in the developing embryonic ectoderm, and even in developing wing discs (Bahrampour et al, 2017). This raises the issue of how SoxN/wor comisexpression can completely override the negative, anti-NB, input from Notch signalling, and whether or not they may be considered to constitute the missing proneural genes.…”

“…We recently found that combinatorial misexpression of a number of NB TFs could trigger ectopic NB generation, both in the embryonic ectoderm and the developing wing discs (Bahrampour et al, 2017). These TFs included SoxN, Wor and Ase, which were particularly potent in combination also with Kruppel (Kr) i.e., UAS-ase, -SoxN, -wor, -Kr (denoted UAS-Quad).…”

“…These TFs included SoxN, Wor and Ase, which were particularly potent in combination also with Kruppel (Kr) i.e., UAS-ase, -SoxN, -wor, -Kr (denoted UAS-Quad). In addition, a combination of dominant versions of three of these TFs i.e., Quad D ) was also highly potent (Bahrampour et al, 2017). To further address the effects of these TFs, we comisexpressed the Quad and Quad D , using the da-Gal4 driver line, which expresses both maternally and ubiquitously zygotically (Wodarz et al, 1995).…”

“…These extremely potent effects of early NB TFs may have gone unnoticed before due to posttranscriptional control of these transgenes. However, these recently generated UAS transgenes were based upon synthetic and codon-optimized cDNAs (Bahrampour et al, 2017). These constructs furthermore omitted the endogenous 5' and 3' UTR, to thereby reduce the possible unwanted negative influence of miRNA control.…”

“…Another gene family with some proneural-like activity is the Snail family; snail, (sna), escargot (esg) and worniou (wor), which act redundantly during CNS development (Ashraf et al, 1999;Ashraf and Ip, 2001;Cai et al, 2001). While, sna, esg, wor triple mutants do not show an apparent reduction in early NB numbers (Ashraf et al, 1999), wor mutants, also heterozygous for sna and esg, display a loss of NBs at later stages (Bahrampour et al, 2017). In addition, co-misexpression of a set of NB factors, which included Wor and SoxN, was shown to be sufficient for generating ectopic NBs broadly in the developing embryonic ectoderm, and even in developing wing discs (Bahrampour et al, 2017).…”