mRNA localisation in endothelial cells regulates blood vessel sprouting
Posted on: 29 August 2018 , updated on: 31 August 2018
Preprint posted on 6 August 2018
rab13 transcripts are targeted to and locally translated at the leading edge of migrating endothelial cells which fine-tunes their protrusive activity during developmental angiogenesis.
Selected by Andreas van Impel
Categories: cell biology, developmental biology
Background
The establishment of polarity on the cellular level by asymmetrically localizing cellular components and molecules including mRNAs plays a central role during various biological processes. For example, the localization of maternal bicoid, oskar and gurken mRNA to opposing ends within the Drosophila oocyte is key for early axis formation in the embryo. Also during asymmetric cell divisions certain proteins and mRNAs are targeted to specific subcellular territories and hence end up in only one of the daughter cells, thereby triggering a distinct developmental program in each of the cells [1].
During cell migration, a polar distribution of proteins regulating the cytoskeleton has been shown to be important for establishing and maintaining directionality. In this context, the accumulation of certain mRNAs to protrusions of different migratory cell types has been reported and it is thought that their local translation contributes to the regulation of actin and focal adhesion dynamics at the leading edge [2]. However, to what extent such dynamic subcellular distributions of certain transcripts are involved in more complex morphogenetic events such as sprouting angiogenesis (a process that generates new blood vessels by sprouting and migration of endothelial cells from pre-existing vessels) has not been explored.
Key findings
In this preprint, Costa and colleagues investigate the presence and functional relevance of asymmetrically located transcripts in migrating endothelial cells. In order to identify such transcripts they employ Human Umbilical Vein Endothelial cells (HUVECs) in a modified Boyden chamber, which allows the separation of cell protrusions from the cell bodies. Subsequent RNA-Seq analysis of these samples revealed a set of 320 mRNAs that are enriched in the protrusions of HUVECs, many of which encode for proteins that are known to accumulate at the leading edge of migrating cells and that are involved in the regulation of cell motility. One of the strongest enrichments within the cell protrusion fraction was detected for the mRNA of the small GTPase RAB13, a known regulator of cellular vesicle trafficking that has been previously reported to be required for directional migration during zebrafish angiogenesis [3]. The authors subsequently show that RAB13 mRNA indeed localizes to the distal most region of endothelial tip cells in vitro and that the transcripts are also actively translated at the leading edge of endothelial cells. By deleting different parts of the RAB13 3’UTR Costa et al. identify a specific 192nt ‘zipcode’ sequence that is essential and sufficient to target mRNAs to the leading edge of migrating endothelial cells. To test these findings also in a more complex in vivo situation, the authors establish a vascular specific in vivo RNA labelling system in zebrafish embryos and show that also during embryonic angiogenic sprouting the rab13 3’UTR sequence is capable of localizing transcripts to the leading edge of endothelial cells.
Finally, to assess a functional role for the specific subcellular localization of rab13 mRNA during angiogenesis, the authors generate zebrafish mutants carrying a deletion within the rab13 3’UTR that strongly reduces the polarized appearance of the transcripts (but does not cause a general loss of the mRNA). Subsequent time-lapse analysis during arterial sprouting and formation of intersegmental blood vessels reveals that in the absence of localized rab13 mRNA the sprouting vessels frequently form transient ectopic branches at distinct positions amongst their migration route, likely reflecting problems to find the correct migration path. These observations suggest that the correct subcellular accumulation of rab13 mRNA at the leading edge provides critical positional information that is required for fine tuning of angiogenic sprouting in vivo.
Why this is cool
The results from Costa et al clearly indicate that the subcellular targeting of certain transcripts is not only an important feature of migrating fibroblasts, neurons or cancer cells, but that this concept of subcellular asymmetry is also required for proper developmental angiogenesis. It is remarkable, that the disturbance of rab13 transcript localization (and not its overall expression) during angiogenesis is sufficient to affect the migratory behaviour of endothelial cells. Interestingly, the morpholino-mediated knock-down of rab13 in zebrafish was previously shown to impede the formation of intersegmental vessels and to interfere with the directionality of tip cells, suggesting that the here reported defects upon mislocalization of rab13 transcripts represent a hypomorphic situation reflecting the importance of transcript localization and local translation of Rab13 at the leading edge for its migratory function. These findings therefore imply that subcellular targeting of certain transcripts during angiogenesis constitutes another level of complexity during the regulation of endothelial cell behaviour and directional migration.
Open questions
- How is the accumulation of rab13 mRNA at the leading edge mediated, which interaction partners are involved in the transport and anchoring of the transcripts?
- What is the local signal preceding the dynamic accumulation of transcripts at a certain site?
- What transcripts other than those encoding cytoskeletal regulators are enriched within protrusions? Are also mRNAs encoding components of certain signalling pathways enriched at the leading edge?
Further reading
[1] Cody, N.E.A. et al., The many functions of mRNA localization during normal development and disease: from pillar to post. WIREs Dev Biol, 2:781–796. (2013)
[2] Liao, G. et al., Control of cell migration through mRNA localization and local translation. WIREs RNA, 6:1–15. (2015)
[3] Wu, C., et al., Rab13-dependent Trafficking of RhoA Is Required for Directional Migration and Angiogenesis. J Biol Chem, 286(26):23511-20. (2011)
doi: https://doi.org/10.1242/prelights.4571
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