Translational repression determines a neuronal potential in Drosophila asymmetric cell division

Abstract

Asymmetric cell division is a fundamental strategy for generating cellular diversity during animal development. Daughter cells manifest asymmetry in their differential gene expression. Transcriptional regulation of this process has been the focus of many studies, whereas cell-type-specific 'translational' regulation has been considered to have a more minor role. During sensory organ development in Drosophila, Notch signalling directs the asymmetry between neuronal and non-neuronal lineages, and a zinc-finger transcriptional repressor Tramtrack69 (TTK69) acts downstream of Notch as a determinant of non-neuronal identity. Here we show that repression of TTK69 protein expression in the neuronal lineage occurs translationally rather than transcriptionally. This translational repression is achieved by a direct interaction between cis-acting sequences in the 3' untranslated region of ttk69 messenger RNA and its trans-acting repressor, the RNA-binding protein Musashi (MSI). Although msi can act downstream of Notch, Notch signalling does not affect MSI expression. Thus, Notch signalling is likely to regulate MSI activity rather than its expression. Our results define cell-type-specific translational control of ttk69 by MSI as a downstream event of Notch signalling in asymmetric cell division.

Extending the dynamic range of transcription factor action by translational regulation

“…Several other proteins acting as translational regulators have been reported in the fly embryo and oocyte [50][51][52][53][54][55][56][57], and in other eukaryotic species [58][59][60], oftentimes in a developmental context. These findings hint at the possibility that the regulatory principle implemented by bicoid protein and caudal mRNA in Drosophila may be at work also in other developmental systems.…”

“…Since these regulatory proteins bind to DNA, it is plausible that they could also bind to mRNA, thereby regulating translation; this is known to happen in the large class of homeodomain proteins [45][46][47] and for the Argonaute family proteins [48,49], for several other proteins that fulfill important functions in the Drosophila embryo and oocyte [50][51][52][53][54][55][56][57], but also in other eukaryotic species [58][59][60] and in prokaryotes [61][62][63][64][65][66][67]. Intuitively, each mRNA molecule could act as an independent sensor of the input concentration, and averaging over these multiple sensors could reduce the input noise and thereby allow for more effective information transmission at low input concentrations.…”

Signal integration during development: Insights from the Drosophila eye

“…Perhaps the need for Notch pathway activation in R7 has the side effect of reducing RTK/Ras/MAPK activity, possibly by transcriptional activation of a MAPK phosphatase as seen in C. elegans (Berset et al, 2001) or else by upregulating yan expression (Rohrbaugh et al, 2002). An alternative explanation is that Notch signaling up-regulates Ttk88 as has been demonstrated in the developing PNS (Guo et al, 1996;Okabe et al, 2001;Pi et al, 2001). Thus, the necessity of using Notch to specify the R7 fate may result in high concentrations of Ttk88 in the presumptive R7.…”

Physiology and pathology of notch signalling system

“…It has been hypothesized that Notch may also have other functions besides regulation of gene expression. It has been demonstrated, for example in Drosophila, that the Notch system changes the function of a cytoplasmic translation regulator (Okabe et al, 2001) and that it may interact with other cell signalling systems (Iso et al, 2003a;Zamurovic et al, 2004).…”