Apoptotic DNA degragdation

DNA degadation is a distinct process during cell death that proceeds simultaneously with cell corpse engulfment. Apoptotic DNA degradation has been proposed to require a multi-nuclease complex, the degadeosome, which is composed of nucleases (CPS-6, CRN-1, CRN-4, CRN-5, CYP-13), and mitochondiral nonnuclease components such as WAH-1.

Programmed cell death

Programmed cell death (PCD), or apoptosis, is an integral component of C. elegans development. During development, 131 cells are fated to die by apoptosis. PCD is easily observed with Nomarski optics in the C. elegans embryo; the nucleus of the apoptotic cell becomes refractile, resembling a flat button, making C. elegans an easy model for following apoptotic cell death. PCD in C. elegans can be divided into three main phases (with participating genes): specification of which cells should live or die (ces-1, ces-2, in general); activation of the cell killing machinery (egl-1, ced-9, ced-4 and ced-3); and an execution phase where the dying cell is dismantled and removed through phagocytosis (ced-1,-2,-5,-6,-7,-10 and-12), which occurs in concert with apoptotic DNA degradation (cps-6, nuc-1). Molecular and biochemical studies in C. elegans revealed programmed cell death mechanisms conserved in humans. The regulatory pathway that controls cell death is composed of conserved cell death activators and inhibitors: EGL-1 and BH3-domain-only proteins, CED-9 and Bcl-2, CED-4 and Apaf-1, and CED-3 and caspases, in nematodes and mammals, respectively. Further the degradation of chromosomal DNA involves a mitochondrial proapoptotic endonuclease: endonuclease G (EndoG), and AIF in mammals and their orthologs CPS-6 and WAH-1 in worms.

Cell migration

Cell movement is an essential cell behavior for metazoan development. When this process is improperly orchestrated it can result in developmental disorders or pathologies such as tumor metastasis. In C. elegans, many cell types including canal associated neurons (CANs), hermaphrodite-specific neurons (HSNs), and Q neuroblasts migrate long distances during embryonic or larval development. Studies in C. elegans have elucidated many of the molecules required for stimulating and guiding the cell. These studies have shown that some directed movement rely on graded chemotactic signaling that is perceived by the cell and transduced to the cell's cytoskeleton. Chemotactic signaling molecules such as UNC-6, an extracellular matrix protein, can act as both an attractant, for cells expressing UNC-5, or as a repellant, for cells expressing UNC-40. Cell migration ultimately requires the regulation of cytoskeletal rearrangements. Studies have demonstrated UNC-73/Trio to be a main activator of Rac signaling in at least some of these migrating cells, which is proposed to drive such intracellular changes.

Unfolded protein response - ER

Correctly folding proteins is a severely complicated process that fails at times, despite the controlled environment of the ER and numerous molecular helpers. Under normal conditions, these misfolded proteins are degraded through the ER-associated degradation (ERAD) mechanism. However, various physiological or environmental stressors can inhibit or overwhelm these normal mechanisms resulting in an increase in the amount of misfolded proteins, which trigger the Unfolded Protein Response (UPR). Organisms have evolved the UPR to handle this ER stress and suppress the toxicity of accumulated misfolded proteins (proteotoxicity). In mammals the UPR attenuates protein synthesis through PERK/PEK1 and increases transcription of folding and ERAD components through activation of potent transcription factors through IRE1 splicing of XBP1 mRNA and ER-stress cleavage of ATF-6. These events ultimately augment folding and enhance degradation capacity of the organelle. In C. elegans, the UPR also activates transcriptional regulators that reduce protein synthesis and increase the number of components necessary to deal with misfolded proteins.

EGF signaling pathway

The Epidermal Growth Factor (EGF) signaling pathway was initially identified by Nobel Prize winner Stanley Cohen who found EGF to be involved in numerous cellular signaling events in mouse development. The single C. elegans EGF ligand, lin-3 and its receptor, lin-28 were initially found in screens for vulval development mutants. Further analysis of similar mutants, led to the identification of the C. elegans core EGFR signaling pathway components, SEM-5/GRB2, SOS-1, LET-60/RAS, LIN-45/RAF, MEK-2/MEK, and MPK-1. Positive regulators of this pathway were subsequently found in suppressor screens, and include KSR-1, SUR-8/SOC-2, and SUR-6. Negative modulators were found in further forward and reverse genetic screens and include UNC-101, SLI-1, GAP-1, SUR-5 and ARK-1 (in conjunction with GRB-2). LIN-3/EGF acts as a signal from the single anchor cell to induce neighboring undifferentiated epithelial cells to adopt the vulval fate during larval development. Impairing this signaling event results in a failure of vulval fate specification, and eventually a vulvaless animal that cannot lay eggs (the "bag of worms" phenotype). As in the mouse, EGF signaling was found to be involved in a number of other processes, although perhaps most importantly it is required for larval survival; homozygous let-23 null worms die at the L1 stage. Further, EGF signaling has been shown to function in coordinating vulva to uterus communication during development, promoting male spicule development, inducing P12.p cell fate in the epithelia, at the same time acting as a physiological signal, promoting ovulatory contractions of the gonad sheath cells, inducing a reversible nervous system quiescence during each larval molt, and regulating protein and calcium homeostasis in the adult worm.