Genetic analysis of the neuronal integrated stress response in developmental plasticity and organismal physiology of C. elegans

Abstract

The genetic study of the C. elegans dauer developmental decision has served as an experimental paradigm for understanding how environmental cues influence organismal physiology through evolutionarily conserved neuroendocrine signaling mechanisms. My genetic characterization of the previously isolated daf-28(sa191) mutant that enters dauer constitutively has revealed cell-nonautonomous roles of conserved stress signaling pathways-the Unfolded Protein Response (UPR) and translational control mediated by eIF2[alpha] phosphorylation. While the cell-autonomous functions of these stress-responsive mechanisms in maintaining cellular homeostasis have been examined, their organismal effects on remodeling development and stress responses remain largely unexplored. Chapter II will highlight the hypotheses and approaches that led to identification of the PEK-1/PERK branch of the UPR, functioning in a pair of chemosensory neurons, as a novel regulator of the dauer developmental decision. Chapter III will examine the systemic effects of eIF2[alpha] phosphorylation, downstream of PERK/PEK-1 activation, in the sensory nervous system on larval development and stress responses. Specifically, the identification of the C. elegans translational regulatory factors that function as molecular determinants of cellular and systemic sensitivity to eIF2[alpha] phosphorylation will be described. Subsections of Chapter III and IV will also highlight genes whose functions can modify the organismal effects of the UPR and eIF2[alpha] phosphorylation: these genes are involved in modulation of ER proteostasis or function in the dauer neuroendocrine pathways that interact with the UPR or eIF2[alpha] phosphorylation. Finally, we proceed to show that alterations in the neuronal eIF2[alpha] phosphorylation status may modulate sensory processing to influence diverse physiological outputs, mimicking the effects of starvation or unfavorable microbial environment. Collectively, results from my study indicate that modulation of the UPR and eIF2[alpha]-mediated translational control in the sensory nervous system confers substantial cell-nonautonomous effects on animal physiology. These findings underscore how molecular events underlying cellular homeostasis, which can be perturbed by fluctuating environmental and developmental conditions, may be co-opted to systemically reprogram organismal stress responses in C. elegans.