Polo kinases regulateC. elegansembryonic polarity via binding to DYRK2-primed MEX-5 and MEX-6

Abstract

During Caenorhabditis elegans embryogenesis, anteroposterior (AP) polarity is established by a hierarchy of PAR proteins (for a review, see Kemphues, 2000). Many of these PAR proteins are asymmetrically localized at the cortex along the AP axis. The asymmetric distribution of PAR proteins determines the position of the first mitotic spindle and the asymmetric localization of key cytoplasmic determinants (for reviews, see Cowan and Hyman, 2004;Lyczak et al., 2002). This results in two daughters that are different in both size and developmental fate: the larger anterior somatic cell, AB, and the smaller posterior germline blastomere, P1. P1 then undergoes a series of three more asymmetric divisions, each giving rise to a germline blastomere (sequentially P2 to P4, termed the P lineage) and a corresponding somatic cell (Fig. 1).PAR proteins regulate spindle position via a G-protein signaling pathway (Colombo et al., 2003;Hess et al., 2004), and cytoplasmic polarity via two maternally supplied proteins, MEX-5 and MEX-6 (Schubert et al., 2000). MEX-5 and MEX-6 are closely related proteins and are both preferentially localized toward the anterior cytoplasm of the one-cell embryo and are enriched in the somatic daughter after the division of each germline blastomere (Cuenca et al., 2003;Schubert et al., 2000). Whereas mex-5 mutants exhibit 100% embryonic lethality, mex-6 mutant embryos are 100% viable with no observable defects (Schubert et al., 2000). However, many molecular defects in mex-5 mutant embryos are dramatically enhanced when mex-6 is also mutated or depleted, suggesting partially redundant functions for these two genes (Schubert et al., 2000). For simplicity, unless specifically noted, we will use MEX-5/6 to refer to MEX-5 and MEX-6.One major function of MEX-5/6 is to restrict the localization of maternally supplied germline proteins, such as PIE-1, POS-1 and MEX-1, to germline blastomeres (Guedes and Priess, 1997;Mello et al., 1996;Schubert et al., 2000;Tabara et al., 1999). In the onecell embryo, as MEX-5/6 become asymmetrically localized anteriorly, PIE-1 becomes localized posteriorly (Cuenca et al., 2003;Mello et al., 1996;Schubert et al., 2000). After cell division, PIE-1 is enriched in P1, and this pattern reiterates in each subsequent Plineage division. The small amount of PIE-1 segregated to the somatic sister after each division is degraded by a ZIF-1-containing CUL-2 E3 ligase complex (DeRenzo et al., 2003;Reese et al., 2000). Both asymmetric distribution of PIE-1 before division, as well as asymmetric degradation after division, require the function of MEX-5/6 (DeRenzo et al., 2003;Schubert et al., 2000). MEX-5/6 are themselves also substrates for this ZIF-1-containing E3 ligase complex (DeRenzo et al., 2003).Before meiosis II, high levels of both PIE-1 and MEX-5/6 proteins are detected uniformly throughout the cytoplasm of oocytes and one-cell embryos ( Fig. 1) (Cuenca et al., 2003;Schubert et al., 2000). This suggests that localization of PIE-1 by MEX-5/6 is a developmentally regulated event ...

MEX-5 asymmetry in one-cellC. elegansembryos requires PAR-4-and PAR-1-dependent phosphorylation

“…However, mutants depleted of MEX-5 and MEX-6 can have variable defects in PAR localization, indicating a complex interplay between the proteins (Cuenca et al, 2003). Recent studies suggest that MEX-5 affects PIE-1 localization in part by binding the polo kinases PLK-1 and PLK-2 (Nishi et al, 2008). PLK-1 is localized to the anterior of the one-cell embryo in a pattern that is similar to, and dependent on, MEX-5 (Chase et al, 2000;Nishi et al, 2008;Rivers et al, 2008).…”

“…Recent studies suggest that MEX-5 affects PIE-1 localization in part by binding the polo kinases PLK-1 and PLK-2 (Nishi et al, 2008). PLK-1 is localized to the anterior of the one-cell embryo in a pattern that is similar to, and dependent on, MEX-5 (Chase et al, 2000;Nishi et al, 2008;Rivers et al, 2008). Both PLK-1 and PLK-2 bind a putative polo-docking site around residue Thr186 in MEX-5; an alanine substitution at Thr186 impairs, although it does not eliminate, MEX-5 function (Nishi et al, 2008).…”

Coordinating cell polarity with cell division in space and time

“…elegans one-cell embryos divide asymmetrically to form a larger anterior cell (AB) and a smaller posterior cell (P1). Cortical PAR polarity controls enrichment of the cytoplasmic mitotic kinase Polo-like kinase (PLK-1) at the anterior of the one-cell embryo [50][51][52]. As a result, AB inherits higher levels of PLK-1 at division.…”

Fertilization and the oocyte-to-embryo transition in C. elegans

“…The complex begins to dissociate when EGG-3 is targeted for degradation by the ubiquitin ligase containing APC/C that is activated at meiotic anaphase I (74). Once MBK-2 is released from the regulatory complex, its substrates include a variety of major regulators of the oocyte-to-embryo transition, including MEI-1, OMA-1, OMA-2, MEX-5, and MEX-6 (82)(83)(84)(85)(86). MEI-1 is necessary for the proper mitotic spindle formation, OMA-1 and OMA-2 are necessary for sequestration of a general transcription factor component, and MEX-5 and MEX-6 are necessary for regulating polarity (82,83,87).…”

“…Once MBK-2 is released from the regulatory complex, its substrates include a variety of major regulators of the oocyte-to-embryo transition, including MEI-1, OMA-1, OMA-2, MEX-5, and MEX-6 (82)(83)(84)(85)(86). MEI-1 is necessary for the proper mitotic spindle formation, OMA-1 and OMA-2 are necessary for sequestration of a general transcription factor component, and MEX-5 and MEX-6 are necessary for regulating polarity (82,83,87). MBK-2 substrates are central in regulating the resumption of the first meiotic division after fertilization and triggering the transition from a quiescent developmental state to one of rapid development and division.…”