Academic journal article Genetics

Mitotic Spindle Positioning in the EMS Cell of Caenorhabditis Elegans Requires LET-99 and LIN-5/numa

Academic journal article Genetics

Mitotic Spindle Positioning in the EMS Cell of Caenorhabditis Elegans Requires LET-99 and LIN-5/numa

Article excerpt

HIGHLY controlled mechanisms of spindle positioning underlie both symmetric and asymmetric cell divisions. In the case of asymmetric divisions, the position of the spindle specifies the plane of division and, thus, is critical for proper segregation of cell fate determinants into the differentially fated daughter cells. In addition, the plane of cell division affects daughter cell placement, which influences the morphogenesis of tissues and organs within an organism. Much of our understanding of spindle positioning has come from studies of asymmetric division in the one-cell Caenorhabditis elegans embryo and Drosophila melanogaster embryonic neuroblasts. Later research in vertebrate epithelial cells provided evidence for the conservation of the spindle positioning pathways. In all of these cell types, intrinsic PAR polarity proteins occupy distinct cortical domains to regulate cytoplasmic asymmetry and spindle positioning. A conserved complex of Ga/GPR/LIN-5 (Ga/Pins/Mud in Drosophila and Ga/ LGN/NuMA in vertebrate cells) anchored at the cell cortex acts downstream of PAR proteins to recruit the microtubule motor protein dynein, which pulls on astral microtubules to physically position the nuclear-centrosome complex and spindle (Hao et al. 2010; Rodriguez-Fraticelli et al 2010; Zheng et al. 2010; Morin and Bellaiche 2011; McNally 2013; Rose and Gonczy 2014; Williams et al. 2014).

LIN-5 (NuMA, Mud) was shown to be a direct link to dynein and GPR-1/2 (LGN, Pins) (Du and Macara 2004; Siller et al. 2006; Couwenbergs et al. 2007; Nguyen-Ngoc et al. 2007). NuMA and Mud have also been shown to be required for spindle positioning in association with additional components, and in some cases without Ga, or LGN/Pins. For example, in the Drosophila sensory organ precursor cell (SOP), the Wnt planar cell polarity pathway orients the spindle both with respect to the plane of the epithelium and on the anterior/posterior (A/P) axis of the organism. The first orientation involves the Ga/Pins/Mud complex, but the latter involves direct recruitment of Mud by the Wnt component, Dishevelled, independent of Ga and Pins (Bellaiche et al. 2001a,b; David et al 2005; Segalen et al 2010). A similar planar cell polarity-directed pathway that requires Dsh, NuMA, and actin regulators aligns spindles during zebrafish gastrulation (Segalen et al. 2010; Castanon et al. 2013). In vertebrate cells that divide in parallel to the substrate, NuMA can also be recruited to the cortex independently of LGN at anaphase. This requires the ERM family proteins, phospholipids, and actin (Kiyomitsu and Cheeseman 2013; Seldin et al. 2013; Kotak et al. 2014; Zheng et al. 2014).

Despite considerable progress, much remains to be learned about mechanisms of spindle positioning, especially in response to multiple signaling pathways. The asymmetric division of the endomesodermal precursor (EMS) cell in the four-cell C. elegans embryo is an excellent model for understanding the coordination of multiple cues. In the EMS cell, the PAR domains exhibit an inner/outer polarity that is dependent on cell-cell contacts (Nance and Priess 2002). Thus, the PAR domains are not aligned with the spindle as they are in the well-characterized one-cell and P1 divisions. Rather, the EMS spindle aligns with the A/P axis in response to partially redundant Wnt and Mes-1 polarity cues that come from the neighboring posterior cell, called P2 (Figure 1A and Figure 2A). In the absence of both cues, the EMS blastomere divides on the left/right (L/R) axis and fails to specify endoderm (Bei et al. 2002).

Genetic experiments showed that the upstream components of the Wnt signaling pathway, such as the Wnt ligand (MOM-2 in C. elegans), the Frizzled receptor (MOM-5), and the Disheveled adaptor proteins (DSH-2 and MIG-5), play a role in EMS spindle positioning (Figure 2A); however, this activity is independent of the transcriptional activation associated with canonical Wnt signaling (Schlesinger et al. …

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