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Zygote polarization in C. elegans

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Zygote polarization is an invariant and crucial process in the development of Caenorhabditis elegans. After the C. elegans oocyte is fertilized, an asymmetric distribution of several cellular components leads to the establishment of the embryonic anterior-posterior (AP) axis. This creates both a molecular and mechanochemical cell polarity in the one-cell embryo[1]. The zygote undergoes several asymmetric cell divisions where the daughter cells from each division differ in size because of this polarity. The first cell divisions give rise to six founder cells from which all the other tissues are derived[2].

The process of polarization in the one-cell zygote occurs in three phases: symmetry breaking, establishment, and maintenance. Symmetry breaking begins soon after fertilization of the oocyte. Approximately 30 minutes after fertilization, the partitioning defective (PAR) proteins become asymmetrically distributed in the zygote[3]. In addition to an asymmetric distribution of the PAR proteins, asymmetric contractility of the actomyosin cortex, and a directed cortical flow are also established in the polarized zygote[4].

This article covers several important factors in establishing and maintaining cell polarity prior to the first cell division in C. elegans development. However, polarization plays an important role in subsequent cell divisions. Cell polarity also plays many important roles in other eukaryotic organisms[5].

History

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C. elegans embryo development imaged by DIC microscopy. Asymmetric cell divisions are clearly visible.

The full embryonic cell lineage of Caenorhabditis elegans was mapped by Sulston and colleagues in 1983[2]. He won the Nobel Prize in Physiology or Medicine in 2002 alongside Sydney Brenner and Robert Horvitz for their work with C. elegans[6]. While studying isolated C. elegans embryos using light microscopy, it was observed that the first cell division results in a larger anterior and smaller posterior cell. These cells were termed AB and P1 respectively. These daughter cells were observed to undergo more asymmetric cell divisions, resulting in the six founder cells: ABal, ABpl, C, MS, P3, and E[2].

Genetic screens in C. elegans embryos resulted in the discovery of several mutants that displayed abnormal cell divisions during early development. These genes were given the name partitioning defective (par). Early studies identified six PAR proteins (PAR-1, PAR-2, PAR-3, PAR-4, PAR-5, and PAR-6) but several other proteins important for the establishment of polarity have since been discovered[7][8][9]. It was later found that PAR proteins are conserved and are crucial for polarization in other eukaryotic cell types beyond C. elegans, including in mammalian cells[1].

Polarization process

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Fertilization and centrosome positioning

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Symmetry breaking is the first phase of zygote polarization. Prior to fertilization, the oocyte has no defined AP axis [10]. After fertilization of the oocyte occurs by sperm entry, the cytoplasm of the cell rearranges, resulting in a flow of material towards the sperm pronucleus and the movement of the pronucleus itself towards the cortex at what will become the posterior pole. The sperm-donated centrosome is visible at the cortex soon after fertilization, which is important for proper polarity establishment. This marks the first signs of an established asymmetry in the embryo[10][11].

Cortical flow during polarity establishment

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Contractile polarity of the cell cortex is another important factor in C. elegans polarity establishment. Disruption of actin or non-muscle myosin class II heavy chain (NMY-2) function prevents PAR asymmetry during polarity establishment[12][4]. Labelling NMY-2 with GFP in embryos shows an actomyosin cortex that is distributed throughout the cell periphery. The cortex contracts and relaxes in a cyclical manner and these contractions are distributed symmetrically throughout the embryo[4]. After symmetry breaking, the sperm pronucleus has localized to the cortex and the sperm microtubule-organizing center is visible (MTOC)[4]. There is evidence supporting that contractility is reduced around the sperm MTOC. This in turn triggers cortical flow that moves actomyosin in the cortex towards the anterior of the embryo. Resulting in an asymmetric distribution of contractions which gives the cortex a distinct shape, where it is smooth in the posterior region and ruffled in the anterior[4][13].  

The establishment of polarity in these cortical ruffles occurs simultaneously with the polarization of PAR proteins. Both the anterior and posterior PAR proteins localize to the cortex and their localizations are dependent on the presence of this cortical flow[4].

Asymmetric distribution of PAR proteins during polarity establishment

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Asymmetric distribution of PAR proteins lead to A-P axis formation at the one-cell stage and an asymmetric cell division into the AB and P1 daughter cells. Black arrows show cortical flow towards the anterior pole.

Polarity establishment in the C. elegans zygote occurs after symmetry breaking. This process is marked by a change in the localization of PAR proteins. Prior to the first embryonic cell division, PAR-3 co-localizes with PAR-6 and atypical protein kinase C (PKC-3) through direct interactions. The PAR-3/PAR-6/PKC-3 complex then localizes to the anterior cell cortex[8][14]. During this phase, PAR-1 and PAR-2 become localized to posterior cortex[3]. This results in the establishment of distinct anterior and posterior domains in the embryo. In experiments where the sperm-donated centrosome is removed prior to polarity establishment, there is no posterior localization of PAR-2. This demonstrates that the centrosome is an important component in establishing polarity. However, removing the centrosomes after asymmetry is already established has no effect on PAR localization[15].

Unlike the PAR proteins described above, PAR-4 and PAR-5 are not asymmetrically distributed and can be found in both the cytoplasm and at the cortex. However, mutating their genes, especially in the case of PAR-5, impacts localization of the anterior complex[16][17].

Apart from the PAR proteins themselves, other proteins also play a role in the establishment and maintenance of PAR protein localization. An example is the GTPase Cdc42. Knocking down cdc-42 with RNAi in zygotes resulted in an inability to properly establish polarity. Removal of Cdc42 resulted in mislocalization of PAR-3 and PAR-6, where these proteins were no longer found exclusively at the anterior cell cortex[18].

Polarity maintenance

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After polarity is achieved in the one-cell zygote, the embryo maintains this state for a short time prior to the first cell division[13]. While the sperm donated centrosome is crucial for the symmetry breaking and establishment phases, it is not essential for the maintenance of polarity after this point [15]. The opposite localizations of the anterior and posterior PAR proteins are maintained by antagonistic interactions between the anterior complex and PAR-2 [3]. In mutants where any one of PAR-3, PAR-6, or PKC-3 function is abrogated, localization of PAR-2 is disrupted[19]. While the importance of PAR proteins in establishing polarity in C. elegans is established, the antagonistic interactions between them are not as well characterized[20].

Cell division

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See also

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Caenoerhabditis elegans

Cell polarity

Cdc42

Asymmetric cell division

References

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  1. ^ a b Goldstein, Bob; Macara, Ian G. (2007-11). "The PAR Proteins: Fundamental Players in Animal Cell Polarization". Developmental Cell. 13 (5): 609–622. doi:10.1016/j.devcel.2007.10.007. PMC 2964935. PMID 17981131. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  2. ^ a b c Sulston, J. E.; Schierenberg, E.; White, J. G.; Thomson, J. N. (1983-11-01). "The embryonic cell lineage of the nematode Caenorhabditis elegans". Developmental Biology. 100 (1): 64–119. doi:10.1016/0012-1606(83)90201-4. ISSN 0012-1606.
  3. ^ a b c Cuenca, Adrian A.; Schetter, Aaron; Aceto, Donato; Kemphues, Kenneth; Seydoux, Geraldine (2003-04-01). "Polarization of the C. elegans zygote proceeds via distinct establishment and maintenance phases". Development. 130 (7): 1255–1265. doi:10.1242/dev.00284. ISSN 0950-1991.
  4. ^ a b c d e f Munro, Edwin; Nance, Jeremy; Priess, James R. (2004-09). "Cortical Flows Powered by Asymmetrical Contraction Transport PAR Proteins to Establish and Maintain Anterior-Posterior Polarity in the Early C. elegans Embryo". Developmental Cell. 7 (3): 413–424. doi:10.1016/j.devcel.2004.08.001. {{cite journal}}: Check date values in: |date= (help)
  5. ^ Gubieda, Alicia G.; Packer, John R.; Squires, Iolo; Martin, Jack; Rodriguez, Josana (2020-10-12). "Going with the flow: insights from Caenorhabditis elegans zygote polarization". Philosophical Transactions of the Royal Society B: Biological Sciences. 375 (1809): 20190555. doi:10.1098/rstb.2019.0555. ISSN 0962-8436. PMC 7482210. PMID 32829680.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ "The Nobel Prize in Physiology or Medicine 2002". NobelPrize.org. Retrieved 2024-12-11.
  7. ^ Kemphues, Kenneth J.; Priess, James R.; Morton, Diane G.; Cheng, Niansheng (1988-02). "Identification of genes required for cytoplasmic localization in early C. elegans embryos". Cell. 52 (3): 311–320. doi:10.1016/S0092-8674(88)80024-2. {{cite journal}}: Check date values in: |date= (help)
  8. ^ a b Hung, Tak-June; Kemphues, Kenneth J. (1999-01-01). "PAR-6 is a conserved PDZ domain-containing protein that colocalizes with PAR-3 in Caenorhabditis elegans embryos". Development. 126 (1): 127–135. doi:10.1242/dev.126.1.127. ISSN 0950-1991.
  9. ^ Etemad-Moghadam, Bijan; Guo, Su; Kemphues, Kenneth J. (1995-12). "Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos". Cell. 83 (5): 743–752. doi:10.1016/0092-8674(95)90187-6. {{cite journal}}: Check date values in: |date= (help)
  10. ^ a b Goldstein, Bob; Hird, Steven N. (1996-05-01). "Specification of the anteroposterior axis in Caenorhabditis elegans". Development. 122 (5): 1467–1474. doi:10.1242/dev.122.5.1467. ISSN 0950-1991.
  11. ^ Bienkowska, Dominika; Cowan, Carrie R. (2012-04). "Centrosomes Can Initiate a Polarity Axis from Any Position within One-Cell C. elegans Embryos". Current Biology. 22 (7): 583–589. doi:10.1016/j.cub.2012.01.064. {{cite journal}}: Check date values in: |date= (help); no-break space character in |first2= at position 7 (help)
  12. ^ Guo, Su; Kemphues, Kenneth J. (1996-08). "A non-muscle myosin required for embryonic polarity in Caenorhabditis elegans". Nature. 382 (6590): 455–458. doi:10.1038/382455a0. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  13. ^ a b Geßele, Raphaela; Halatek, Jacob; Würthner, Laeschkir; Frey, Erwin (2020-01-27). "Geometric cues stabilise long-axis polarisation of PAR protein patterns in C. elegans". Nature Communications. 11 (1): 539. doi:10.1038/s41467-020-14317-w. ISSN 2041-1723. PMC 6985163. PMID 31988277.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ Dickinson, Daniel J.; Schwager, Francoise; Pintard, Lionel; Gotta, Monica; Goldstein, Bob (2017-08). "A Single-Cell Biochemistry Approach Reveals PAR Complex Dynamics during Cell Polarization". Developmental Cell. 42 (4): 416–434.e11. doi:10.1016/j.devcel.2017.07.024. PMC 5575849. PMID 28829947. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  15. ^ a b Cowan, Carrie R.; Hyman, Anthony A. (2004-09). "Centrosomes direct cell polarity independently of microtubule assembly in C. elegans embryos". Nature. 431 (7004): 92–96. doi:10.1038/nature02825. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Watts, Jennifer L.; Morton, Diane G.; Bestman, Jennifer; Kemphues, Kenneth J. (2000-04-01). "The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry". Development. 127 (7): 1467–1475. doi:10.1242/dev.127.7.1467. ISSN 0950-1991.
  17. ^ Morton, Diane G.; Shakes, Diane C.; Nugent, Staci; Dichoso, Daryl; Wang, Wenfu; Golden, Andy; Kemphues, Kenneth J. (2002-01). "The Caenorhabditis elegans par-5 Gene Encodes a 14-3-3 Protein Required for Cellular Asymmetry in the Early Embryo". Developmental Biology. 241 (1): 47–58. doi:10.1006/dbio.2001.0489. {{cite journal}}: Check date values in: |date= (help)
  18. ^ Kay, Amanda J.; Hunter, Craig P. (2001-04). "CDC-42 regulates PAR protein localization and function to control cellular and embryonic polarity in C. elegans". Current Biology. 11 (7): 474–481. doi:10.1016/S0960-9822(01)00141-5. {{cite journal}}: Check date values in: |date= (help)
  19. ^ Boyd, Lynn; Guo, Su; Levitan, Diane; Stinchcomb, Dan T.; Kemphues, Kenneth J. (1996-10-01). "PAR-2 is asymmetrically distributed and promotes association of P granules and PAR-1 with the cortex in C. elegans embryos". Development. 122 (10): 3075–3084. doi:10.1242/dev.122.10.3075. ISSN 0950-1991.
  20. ^ Goehring, Nathan W.; Hoege, Carsten; Grill, Stephan W.; Hyman, Anthony A. (2011-04-25). "PAR proteins diffuse freely across the anterior–posterior boundary in polarized C. elegans embryos". Journal of Cell Biology. 193 (3): 583–594. doi:10.1083/jcb.201011094. ISSN 0021-9525. PMC 3087016. PMID 21518794.{{cite journal}}: CS1 maint: PMC format (link)
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