Identification of Factors That Establish Asymmetry and Cell-death Fate in the NSM lineage in Caenorhabditis elegans

During the development of a C. elegans hermaphrodite, 131 of the
1090 cells generated die due to programmed cell death, an important
process conserved throughout the animal kingdom. Although a genetic
pathway for programmed cell death has been established in C.
elegans, not much is known about the signals that trigger cell
death in cells destined to die. One particular cell-death event,
the death of the NSM sister cell, occurs about 430 min after the
first division of the zygote, just 20 min after its progenitor cell
has undergone an asymmetric cell division. The sister of the NSM
sister cell, the NSM, however, survives and differentiates into a
serotonergic neuron located in the pharynx. Here, I show that the
cell-death activator egl-1 is expressed in the NSM sister cell,
which is destined to die, but not in the surviving NSM. In
addition, using a candidate gene approach, I found that in
hlh-2(bx108lf); hlh-3(bc248lf) animals, 30% of the NSM sister cells
survive. This observation suggests that the NSM sister cell death
is at least partially dependent on the activity of hlh-2 and hlh-3,
which code for bHLH transcription factors. These and additional
results suggest that egl-1 expression is directly activated in the
NSM sister cell by a heterodimer composed of HLH-2 and HLH 3, which
binds to a specific cis-regulatory region of the egl-1 locus. In
order to identify additional factors that contribute to the NSM
sister cell death, I performed a forward genetic screen. In
particular, I screened for mutations that enhance the NSM sister
cell survival caused by hlh-2(bx108). This screen resulted in the
identification of mutations in at least six genes not previously
implicated in this cell-death event. One of these mutations, bc212,
is a loss-of-function mutation in the gene dnj-11. dnj-11 codes for
a protein with a J domain, which is found in chaperones, as well as
two SANT domains, which are implicated in transcriptional
regulation. dnj-11 is an essential gene expressed in most if not
all cells. Furthermore, it acts in the NSM sister cell death
pathway by negatively regulating the activity of the snail-like
gene ces-1. dnj-11 is required for the ability of the NSM mother
cell to divide asymmetrically. I propose that dnj-11 promotes the
death of the NSM sister cell by establishing polarity in the NSM
mother cell. Moreover, I present evidence that the snail-like ces-1
gene is involved in establishing polarity in the NSM mother cell as
well, revealing a new function of ces-1 in C. elegans.