millepattes micropeptides are an ancient developmental switch required for embryonic patterning
Preprint posted on September 03, 2018 https://www.biorxiv.org/content/early/2018/09/03/376111
Micropeptides (very short proteins) play important roles in development, but have received relatively little attention thus far. One well-characterised exception is the set of peptides encoded by the insect-specific millepattes (mlpt) gene [a.k.a. tarsalless (tal) or polished rice (pri) in Drosophila]. Mlpt peptides recruit a ubiquitin ligase, Ubr3, to a transcription factor called Shavenbaby (Svb) [a.k.a. Ovo], targeting its N-terminal repression domain for cleavage by the proteasome. This post-translational modification turns Svb into an activator, changing its regulation of downstream genes.
Mlpt, Svb, and Ubr3 therefore form a functional module, because production of the activator form of Svb depends on coincident expression of all three components. Accordingly, perturbing any of the three components leads to similar sets of phenotypes – for example, pri, svb, and ubr3 mutants all cause a loss of denticles in the Drosophila larval cuticle.
Interestingly, the mlpt locus was first identified through a dramatic segmentation phenotype in the beetle Tribolium, but no comparable segmentation function has been found for tal/pri or svb in Drosophila. In Tribolium, Mlpt seems to be involved in the switch from thoracic to abdominal segmentation, as RNAi against mlpt results in truncated embryos with extra pairs of legs (“mille-pattes” means “centipede” in French!) Now, this preprint explores the conservation of this segmentation role across insects.
Ray, Rosenberg and colleagues analysed the function of mlpt, svb, and ubr3 in a number of non-drosophilid model insects – namely Tribolium, the true bugs Gerris and Oncopeltus, and the parasitoid wasp Nasonia – using CRISPR and RNAi. In each case they found that all three genes were implicated in segmentation, epidermal patterning, and proximo-distal patterning of the legs, indicating that the Mlpt/Svb/Ubr3 module is conserved across hundreds of millions of years of evolution, and plays a similar set of developmental roles in diverse insects.
They also analysed the expression of the three genes by in situ hybridisation. ubr3 is ubiquitously expressed in embryos, but mlpt and svb exhibit dynamic and largely complementary expression patterns, presumably restricting the Svb activator form to the few tissues and stages where mlpt and svb domains overlap. Significantly, the timing and location of the segmentation-related expression domains seemed to correlate with the onset of sequential segment addition in each species (rather than with a given axial position), suggesting that the Mlpt/Svb/Ubr3 module might be involved in triggering a developmental switch between simultaneous and sequential modes of segment patterning.
But how to explain the lack of a segmentation phenotype in Drosophila? Although mlpt [tal/pri] has a stripy expression pattern in the Drosophila blastoderm, suggestive of a link to segmentation, maternal svb expression fades early in embryogenesis, meaning that Mlpt and Svb activity does not normally overlap. However, the authors found that misexpression of Svb during segmentation stages resulted in a disruption to segment patterning, indicating that although the Drosophila Mlpt/Svb/Ubr3 module no longer plays an active role in segmentation, it retains an ancestral potential to regulate segmentation genes.
The findings in this study are an important reminder that in many respects the Drosophila embryo is a poor model for insect segmentation. Genes like mlpt and svb have lost their segmentation roles in Drosophila, although they seem to be intact in most other insects. In addition, the clear importance of post-translational regulatory processes in these other insects contrasts with the mainly transcriptional level of regulation characterised for Drosophila segmentation.
However, it’s important to note that it’s still not at all clear what the Mlpt/Svb/Ubr3 module actually does to regulate segmentation! Based on their current observations, the preprint authors raise the intriguing hypothesis of the Mlpt/Svb/Ubr3 module being a developmental switch between simultaneous and sequential segmentation modes, which will make for a fascinating follow-up project. Ironically, an obvious place to start the investigation will be with the Drosophila blastoderm; identifying direct targets of the Mlpt/Svb/Ubr3 module by determining which segmentation genes are the first to be misregulated in the presence of ectopic Svb.
Zanet J, Benrabah E, Li T, Pélissier-Monier A, Chanut-Delalande H, Ronsin B, Bellen HJ, Payre F, Plaza S. (2015) Pri sORF peptides induce selective proteasome-mediated protein processing. Science 349(6254):1356-1358
Savard J, Marques-Souza H, Aranda M, Tautz D. (2006). A segmentation gene in Tribolium produces a polycistronic mRNA that codes for multiple conserved peptides. Cell 126(3): 559-569
Rosenberg MI, Brent AE, Payre F, and Desplan C. (2014). Dual mode of embryonic development is highlighted by expression and function of Nasonia pair-rule genes. eLife 3:e01440.
Posted on: 12th September 2018 , updated on: 13th September 2018Read preprint
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