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Open Access Publications from the University of California

The Regulation of Q Lineage Asymmetric Cell Division

  • Author(s): Williams, Falina J.
  • Advisor(s): Garriga, Gian
  • et al.

Asymmetric cell division (ACD) is a process that generates cell diversity. Both intrinsic and extrinsic mechanisms can distribute developmental potential asymmetrically to generate daughter cells of different fates and position the cleavage furrow asymmetrically to generate cells of different sizes. In chapter I, I review the field of ACD with a focus on the divisions of the Sensory Organ Precursors and the Neuroblasts of the fruitfly Drosophila melanogaster and the early embryonic division of the zygote and the EMS blast cell of the nematode Caenorhabditis elegans. I also focus on the ACDs that produce apoptotic cells in C. elegans.

In Chapter II, I discuss my work on the role of the AGAP homolog CNT-2 in the Q lineage divisions that produce neurons and cells fated to die. AGAPs are a class of Arf GAPs that are modular in structure. CNT-2 was shown previously to regulate the asymmetry of Q.p division, which produces a larger oxygen sensing neuron and a cell fated to die. cnt-2 acts cell autonomously in a genetic pathway with arf-1.2 and arf-6 (Singhvi et al. 2011). CNT-2 function in Q.p was also shown to require ArfGAP activity. I found that several of the CNT-2 domains are necessary for Q.p cleavage furrow placement to generate daughter cells of different sizes and for specification of the apoptotic fate. The CNT-2 Pleckstrin Homology (PH) domain is essential for CNT-2 function, and mutational analysis suggests that the PH domain functions through interactions with phosphoinositide signaling molecules. I also show full CNT-2 activity requires both the N-terminus and the G protein-like domain (GLD) and that these domains also appear to regulate the stability of CNT-2 since removing them leads to increased levels of the mutant protein. The ankyrin domains are also necessary for full CNT-2 function and also regulate protein stability since deleting them leads to a reduction of CNT-2 levels. When expressed in intestinal cells, CNT-2 localizes to the apical membrane and to puncta. The puncta of CNT-2 and the endosomal protein RAB-5 are often adjacent to one another suggesting that CNT-2 might either deliver cargo to or from the RAB-5 endosomal compartment. This finding is consistent with previous suggestions that CNT-2 acts in an endocytic pathway. Finally, I show that CNT-2 can act as a GAP for ARF-1.2 and ARF-6 but not ARF-3. These findings are consistent with previous genetic interactions between mutations in cnt-2 and either arf-1.2 or arf-6.

In Chapter III, I discuss my work on determine the role or Wnts and the C. elegans Van Gogh homolog VANG-1 in the Q lineage. Wnts are evolutionarily conserved secreted glycoproteins that are utilized throughout development and play a role in ACD (Munro and Bowerman 2009). During C. elegans development, Wnts regulate asymmetric divisions by controlling the distributions of the β-catenin SYS-1 and the LEF/TCF homolog POP-1 (Mizumoto and Sawa 2007). They can also regulate the orientation of the spindle (Walston and Hardin 2006). The ACDs of the Q.a and Q.p neuroblasts give rise to a larger daughter that lives and a smaller cell destined to die. Previous unpublished work found that two homologs of the Frizzled class of Wnt receptors, LIN-17 and MOM-5, are necessary for both apoptotic fates, for the asymmetric distribution of POP-1 in the Q.a and Q.p daughter cells, and for the asymmetric position of the Q.a and Q.p furrows that produce daughter cells of different sizes. In a search for the Frizzled ligands, I discovered that both Wnts and VANG-1, which can also bind to Frizzled receptors, regulate the fates of cells in the Q lineage and the asymmetric distribution of POP-1 early in the Q lineage. However, neither Wnts nor VANG-1 affects POP-1 asymmetry in Q.p, and neither regulates furrow localization. VANG-1 is expressed in the Q lineage and neighboring cells but does not act in the Q lineage to regulate asymmetric cell division, but rather in the neighboring seam cells during late embryonic and early larval development. These findings suggest that the vang-1 mutant defects in the fates of Q-lineage neurons and apoptotic cells from earlier detects in the lineage. My results also suggest that the roles of the Frizzleds LIN-17 and MOM-5 in the regulation of the Q.a and Q.p asymmetry occur independent of the Wnts and VANG-1.

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