PLK1- and PLK4-mediated asymmetric mitotic centrosome size and positioning in the early zebrafish embryo
Posted on: 5 May 2020
Preprint posted on 14 April 2020
Article now published in Current Biology at http://dx.doi.org/10.1016/j.cub.2020.08.074
Big spot, little spot: How an asymmetric pair of mitotic centrosomes mediates early cell divisions in zebrafish
Selected by Maiko KitaokaCategories: cell biology, developmental biology
Background
Early embryogenesis begins with a very large single cell that goes through fast divisions to create smaller and smaller cells. However, large cells provide a challenge to cellular machinery – how can it handle all of the extra cytoplasmic space to build and maintain the crucial role of the mitotic spindle? While mechanisms of spindle assembly and positioning have been studied in other systems, it’s still unclear how the mitotic spindle can orient itself when the cell is very large, and how it can adapt to the rapidly changing cell size of early embryonic divisions.
Rathbun et al have discovered that large zebrafish early embryo cells have asymmetric centrosomes, such that one is quite large, approximately 250 µm2! This large centrosome scales with cell size, and is regulated by Polo-like kinases 1 and 4 (PLK1, PLK4 respectively). These large centrosomes could potentially be used to assist astral microtubules to reach the cell cortex and anchor the mitotic spindle.
Key findings
The authors began with an evolutionary comparison between the invertebrate nematode worm, C. elegans, and vertebrate zebrafish, D. rerio, to find out how both organisms handle their early embryonic divisions and determine their conservation. Both organisms decreased cell area during the early divisions, though the magnitude of this decrease was constant in zebrafish and was less drastic over time in C. elegans, suggesting that while cell size always decreases, the magnitude can differ between organisms. Similarly, the cell length continued to decrease with every division, but the mitotic spindle does not shorten at the same rate. For both organisms, this leads the spindle to occupy a higher percentage of the cell length in later divisions, and the distance between centrosomes and the cell membrane also decreased. Both organisms scaled the cell length more closely with the mitotic centrosome area, rather than spindle length. Despite their evolutionary distance and size differences, early cell divisions in both worms and fish still reveal a conserved trend to change cell and spindle dimensions through early embryogenesis.
Surprisingly, zebrafish centrosomes were very large, and demonstrated a unique wheel-like structure of ɣ-tubulin. These centrosomes were also marked with centrin (a centriole marker). Intriguingly, the zebrafish mitotic centrosomes were asymmetric in size, with the larger centrosome always pointing towards the midline of the embryo’s cell grid. This was not observed in C. elegans. In characterizing this asymmetry, Rathbun et al discovered that the larger centrosome is more than 2-fold larger, and this asymmetry is maintained through cell division. Pericentriolar material (PCM) localization by ɣ-tubulin was also asymmetric, consistently biased toward the midline of the embryo.
Polo-like kinases (PLK) 1 and 4 are particularly important in centrosome function and PCM assembly. Both are maternally supplied in the early zebrafish embryo, though levels of PLK4 are very low. By microinjecting small molecule inhibitors of either PLK1 or 4, the authors were able to disrupt directional positioning of the centrosomes. The overall size of the centrosome and PCM increased, and the size difference between the two mitotic centrosomes decreased. This suggests that PLK1 and 4 regulate the structure and asymmetry of centrosomes, as well as the position of the larger centrosome. Incredibly, some of these embryos survived beyond embryogenesis, although they presented several developmental defects, including heart edema, small eyes, and elongation defects.
Overall, the authors demonstrate the conservation of cell size decreases and scaling between centrosome and cell size in early embryos. Moreover, they discovered a unique centrosome pattern in zebrafish and revealed a new asymmetry in mitotic centrosomes in zebrafish embryos. Perhaps there’s more to the early rapid, synchronous cleavages than previously believed!
Questions for the authors
Perhaps this is naïve, but what is the significance of centrin and ɣ-tubulin colocalization in the large centrosomes? Is this not expected in a centrosome? Also, are there any hints as to why the centrosome has this unique wheel-like structure, or what purpose the structure serves?
Is there more microtubule nucleation, or other associated asymmetries, observed with the larger centrosome? Can you speculate on why cells might want more nucleation (or other asymmetries) towards the embryo midline?
Relatedly, is the asymmetry of centrosomes leading to asymmetric cell divisions as well, perhaps serving as early indicators of different cell lineages that are being established? Are the defects seen later in development upon inhibitor treatment a result of incorrect establishment of specific germ layers or cell lineages?
Upon inhibitor treatment, the positioning of the larger centrosome seems to become more random. What determines the size of the centrosomes when PLK1/4 are inhibited? It seems that perhaps PCM regulation is involved, but it’s unclear if there’s an existing bias for one centrosome to be larger than the other?
How conserved is this phenomenon of asymmetric centrosomes (doesn’t seem to be the case in C. elegans)? If other organisms have asymmetric mitotic centrosomes, is it in the early embryo or a different context?
doi: https://doi.org/10.1242/prelights.18795
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