Cytoplasmic localization and asymmetric division in the early embryo of Caenorhabditis elegans

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Erik E. Griffin

Published Online: Mar 11 2015

DOI: 10.1002/wdev.177

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During the initial cleavages of the Caenorhabditis elegans embryo, a series of rapid and invariant asymmetric cell divisions pattern the fate, size, and position of four somatic blastomeres and a single germline blastomere. These asymmetric divisions are orchestrated by a collection of maternally deposited factors that are initially symmetrically distributed in the newly fertilized embryo. Maturation of the sperm‐derived centrosome in the posterior cytoplasm breaks this symmetry by triggering a dramatic and highly stereotyped partitioning of these maternal factors. A network of conserved cell polarity regulators, the PAR proteins, form distinct anterior and posterior domains at the cell cortex. From these domains, the PAR proteins direct the segregation of somatic and germline factors into opposing regions of the cytoplasm such that, upon cell division, they are preferentially inherited by the somatic blastomere or the germline blastomere, respectively. The segregation of these factors is controlled, at least in part, by a series of reaction–diffusion mechanisms that are asymmetrically deployed along the anterior/posterior axis. The characterization of these mechanisms has important implications for our understanding of how cells are polarized and how spatial organization is generated in the cytoplasm. WIREs Dev Biol 2015, 4:267–282. doi: 10.1002/wdev.177 This article is categorized under: Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization Establishment of Spatial and Temporal Patterns > Gradients Early Embryonic Development > Fertilization to Gastrulation

(a) Lineage of the early Caenorhabditis elegans embryo. Beginning with the zygote P₀, P blastomeres divide asymmetrically along the anterior/posterior axis to generate a somatic daughter cell (AB, EMS, C and D) and a germline blastomere (P₁, P₂, P₃, and P₄, marked in green). P₄ divides symmetrically at the ∼100‐cell stage giving rise to Z2 and Z3 that proliferate post‐embryonically to generate the germline. Germline blastomeres are smaller and proceed through the cell cycle more slowly than their somatic sisters. (b) Schematic depicting the initial cleavages of the early embryo in which P blastomeres are colored green and their somatic sisters, AB, EMS, C, and D, are colored gray. Sister cells are connected with a short line. The embryo is roughly 50 µm in length along the anterior/posterior axis. In all figures, embryos are oriented with the anterior to the left and the posterior to the right.

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Temporal and spatial control of ZIF‐1 translation leads to CCCH finger degradation in somatic blastomeres. ZIF‐1 is part of an E3 ubiquitin ligase complex that targets PIE‐1, POS‐1, and MEX‐1 for degradation by the proteasome. zif‐1 mRNA is present throughout the germline and the early embryo, but ZIF‐1 activity is present only in somatic blastomeres. In oocytes and the zygote, ZIF‐1 translation is repressed by OMA‐1/2 and SPN‐2. This repression is relieved by the activation of MBK‐2 at the end of meiosis, which dissociates SPN‐2 from the zif‐1 3′UTR and marks OMA‐1/2 for degradation by the first cell division. The asymmetric inheritance of POS‐1 and MEX‐5/6 during asymmetric P cell divisions leads to zif‐1 translation in somatic blastomeres, where high levels of MEX‐5/6 prevent POS‐1 from repressing zif‐1 translation. In germline blastomeres, high levels of POS‐1 repress ZIF‐1 translation, thus preventing degradation of PIE‐1, POS‐1, and MEX‐1.

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The partitioning of P granules in the Caenorhabditis elegans zygote results from local control of P granule assembly and disassembly. The high concentration of MEX‐5/6 in the anterior promotes P granule disassembly. In the posterior cytoplasm, PAR‐1 reduces the concentration of MEX‐5/6, thus promoting P granule stability and assembly. During mitosis, PPTR‐1 is required to stabilize P granules by preventing unknown, MEX‐5/6‐independent mechanisms from disassembling P granules. PAR‐1 also appears to have a role in stabilizing P granules that is distinct from its role in segregating MEX‐5/6 to the anterior. The mechanisms by which MEX‐5/6, PAR‐1, and PPTR‐1 control P granule assembly and disassembly are not known. Diffuse P granule components are depicted in light blue, and P granules are depicted as blue foci.

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The contributions of MEX‐5 and MEX‐6 to the patterning of the early embryo. The PAR proteins control the segregation of MEX‐5/6 to the anterior cytoplasm in the polarized zygote. MEX‐5/6 feedback on the PAR proteins to promote the establishment of the cortical PAR domains through an unknown mechanism. In wild‐type embryos (left), MEX‐5/6 act to restrict the activity of the germ plasm to the P blastomeres. MEX‐5/6 are required for the segregation of germ plasm CCCH proteins (green) and P granules (blue) to the posterior cytoplasm in the zygote. MEX‐5/6 also controls the segregation of PLK‐1/2 to the anterior cytoplasm in the zygote. PLK‐1/2 are inherited preferentially by AB and promote the relatively rapid progression of AB into mitosis. In somatic cells (in the four‐cell embryo, for example), MEX‐5/6 are required for the degradation of germ plasm mRNAs and for the degradation of germ plasm CCCH proteins. In mex‐5/6 mutant embryos (right), the PAR domains form slowly, but typically reach the normal domain position. However, mex‐5/6 mutant embryos fail to establish cytoplasmic asymmetries, including the segregation of the germ plasm and PLK1/2 and the degradation of germ plasm factors in somatic cells.

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The establishment of cortical PAR polarity in the Caenorhabditis elegans zygote. Before polarization, the anterior PAR proteins (blue) are concentrated at the cell cortex where they prevent the cortical association of the posterior PARs (brown). The maturation of the centrosome triggers two symmetry breaking pathways. In the actomyosin pathway, an unknown cue initiates cortical actomyosin flows that sweep the anterior PARs toward the anterior and allow the posterior PARs to access the posterior cortex. In the PAR‐2/microtubule pathway, centrosomally nucleated microtubules protect PAR‐2 from PKC‐3 phosphorylation, thus allowing PAR‐2 to establish a small posterior domain near the centrosome. In the ∼10 min following symmetry breaking, the interface between the two PAR domains moves toward the anterior until it reaches the midpoint along the A/P axis. The anterior and posterior PAR proteins diffuse laterally on the cortex and exchange between the cortex and cytoplasm. The anterior and posterior PAR proteins antagonize each other's cortical association (‘Mutual Exclusion’), thus preventing the mixing of the two domains.

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The distribution of the PAR proteins and cytoplasmic factors during the first two embryonic cleavages. Before polarization, the anterior PARs (Blue) occupy the entire cortex, while the posterior PARs (Brown) concentrate in the cytoplasm. Concurrent with the establishment of PAR polarity, MEX‐5/6 and the germ plasm components PIE‐1, POS‐1, MEX‐1, and P granules are partitioned to opposing regions of the cytoplasm, leading to their asymmetric inheritance by somatic (AB and EMS) and germline (P₁ and P₂) blastomeres. The low concentrations of PIE‐1, POS‐1, and MEX‐1 that are inherited by somatic blastomeres are rapidly degraded. Unlike POS‐1 and MEX‐1, PIE‐1 concentrates in the nuclei of germline blastomeres where it acts as a global transcriptional repressor. The CCCH finger proteins OMA‐1/2 are symmetrically distributed in the zygote and are degraded beginning at the first cell division. For simplicity, the enrichment of the cytoplasmic proteins in P granules, the association of MEX‐5/6 and PIE‐1 with centrosomes, and the localization of the PARs to cell–cell contacts in the four‐cell embryo are not depicted. The posterior displacement of the mitotic spindle generates somatic blastomeres that are larger than their germline sisters. Sister cells are connected by a short line (e.g., P₂ and EMS).

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Cytoplasmic localization and asymmetric division in the early embryo of Caenorhabditis elegans

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