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8 Nazly Morales Cocinera
However, the mechanism of how DNJ-11 functions to establish polarity in the NSM mother cell is currently rather unclear. It is likely that DNJ-11 functions indirectly. One reason is that, genetically, dnj-11 negatively regulates the snail-like gene ces-1 in the NSM sister cell death pathway, and altered ces-1 function also impairs the asymmetric division of the NSM mother cell. In ces-1(gf) animals, in which ces-1 is proposed to be upregulated, the NSM sister cell and the NSM are of equal size. This observation shed new light on our model of the mechanism that regulates the NSM sister cell death. So far, CES-1 was proposed to be able to act as a direct transcriptional repressor of egl-1 in the NSM sister cell. However, ces-1 might have a second, distinct function, which is in establishing polarity in the NSM mother cell. Evidence that Snail-like proteins function in asymmetric cell division, comes from studies in Drosophila. The loss of snail familygenes has been shown to cause defects in the asymmetric division of neuroblasts. During the development of the Drosophila
central nervous system (CNS), neuroblasts delaminate from the neuroectoderm. These neuroblasts are polarized and divide asymmetrically resulting in two daughter cells of different size. As the large apical daughter cell retains neuroblast identity, and repeatedly undergoes asymmetric divisions, these neuroblasts exhibit stem cell property. The small basal/lateral daughter cell, on the other hand, becomes the
Discussion ganglion mother cell (Lu et al., 2000). Mutants simultaneously lacking the function of three snail family genes, snail, escargot, and worniu, are severely defective in the neuroblast asymmetry (Cai et al., 2001). sna/esg/wor-deficient embryos have delayed and decreased expression of inscutable (insc), as well as Insc translation is inhibited. Insc is required for the correct localization of proteins and mRNA of cell fate determinants like Pros and Numb, and also required for the proper orientation of the spindle (Lu et al., 2000). It was suggested that Snail family proteins regulated Insc at the transcriptional level as well as at the translational level, and that this regulation most likely occurs indirectly. Consequently, the disruption of neuroblast polarity in
sna/esg/wor-deficient embryos is caused by the lack of Insc. However, insc mutants display a less severe phenotype than sna/esg/wor-deficient mutants. Therefore, it has been proposed that the snail family of genes acts in two distinct pathways, a
insc-dependent and an insc-independent pathway. A different study suggested that Snail, Esg, and Wor are required for both the expression of insc and the expression of
string, a gene encoding a cdc25 phosphatase, in the neuroblasts. Both pathways are necessary for the asymmetric cell division of these neuroblasts (Ashraf and Ip, 2001). Based on these studies in Drosophila, it is possible that ces-1 function is required for establishing polarity in C. elegans. One can speculate that CES-1 has two distinct roles in the death of the NSM sister cells. First, it is likely that CES-1 can directly repress egl-1 expression, as discussed above. Additionally, CES-1 might function already in the NSM mother cell. Possibly, CES-1 regulates genes that are required to establish polarity in the NSM mother cell, similar to Snail family proteins in
Drosophila. Excess amounts of CES-1 caused by a gf mutation result in the failure of the NSM mother cell to divide unequally, whereas a similar phenotype is observed in
Drosophila neuroblasts lacking the function of certain Snail family proteins. However, these phenotypes are not necessarily contradictory. Elevated levels of CES-1 might cause an upregulation of a factor functionally homologous to the
Drosophila Insc, which is required for the proper localization of fate-determining factors to one side of the cell. Elevated levels of this factor can cause a disruption of the localization of these fate-determining factors, similar to a disruption caused by the lack of that factor. Therefore, loss-of-function as well as gain-of-function mutations in
Discussion shown that the loss as well as the overexpression of DSH-2 results in a defect in asymmetric cell division causing a duplication of PHA neurons (Hawkins et al., 2005).
A lf mutation in ces-1(lf) does not result in a NSM sister cell survival phenotype nor does it result in the inappropriate death of the NSM. It remains to be determined, however, whether in ces-1(lf) mutants the NSM mother cell still divides asymmetrically as in wild-type. It is very likely that CES-1 functions redundantly with other factors. As shown in Drosophila, eliminating the function of the
snail-family genes snail, wor, or esg does not result in a polarity defect in neuroblasts, however, eliminating the function of all three genes simultaneously causes symmetric divisions (Ashraf and Ip, 2001; Cai et al., 2001). The C. elegans genome encodes three proteins belonging to the Snail superfamily of zinc finger transcription factors, which are CES-1, K02D7.2 and C55C2.1 (Nieto, 2002). However, in triple lf mutants the NSMs survive and the NSM sister cells die like in wild type. It remains to be tested whether the division of the NSM mother cell is asymmetric with respect to size in the triple lf mutant.
However, it also might be possible that CES-1 acts together with proteins of other families. A candidate is the Hairy-like bHLH transcription factor LIN-22, as it has been shown that the Drosophila orthologs of CES-1 and LIN-22, Scratch and Deadpan, act together. A null mutation in scratch results in a reduced number of photoreceptors in the eye, which is significantly enhanced in embryos lacking the function of both scratch and deadpan. Lf mutations of deadpan alone, however, do not cause a significant phenotype, indicating that both genes act redundantly (Roark et al., 1995). A ces-1; lin-22 double mutant most likely is embryonic lethal, which impedes the analysis of the role of ces-1 and lin-22 in the regulation of the NSM sister cell death.