Your neighbours matter - non-autonomous control of apoptosis in development and disease

Abstract

Traditionally, the regulation of apoptosis has been thought of as an autonomous process in which the dying cell dictates its own demise. However, emerging studies in genetically tractable multicellular organisms, such as Caenorhabditis elegans and Drosophila, have revealed that death is often a communal event. Here, we review the current literature on non-autonomous mechanisms governing apoptosis in multiple cellular contexts. The importance of the cellular community in dictating the funeral arrangements of apoptotic cells has profound implications in development and disease.

Figure 1

Apoptosis pathways in various organisms. (a) In C. elegans, a stimulus (e.g. CEP-1/p53 in response to DNA damage) activates the core apoptosis pathway through transcriptional induction of EGL-1, leading to a suppression of CED-9. Suppression of CED-9 results in the release of CED-3 and formation of a complex with CED-4. This complex leads to apoptosis. (b) Apoptosis in D. melanogaster can be initiated autonomously or through receptor-mediated pathways. Activation of antagonists of inhibitors of apoptosis (IAP) including Hid, Rpr, Grim or Skl leads to inhibition of Diap1. Consequently, initiator caspases (Dronc and Dredd) are activated and lead to activation of effector caspases (Drice, Dcp-1 and Decay) and apoptosis. This pathway can be influenced by extrinsic factors including Eiger, upstream of JNK. (c). In mammals, apoptosis can be initiated intrinsically or extrinsically. The intrinsic pathway is similar to C. elegans and D. melanogaster pathways. In the extrinsic pathway, activation of a ‘death' receptor leads to formation of the death-inducing signalling complex (DISC) and activation of caspases 8 and 10, leading to apoptosis

Figure 2

Engulfment pathways regulate core apoptosis machinery in C. elegans. (a) ‘Eat-me' signals from the dying cell signals to phagocytic cell in order to initiate engulfment. Engulfment factors from engulfing cells can act to permit completion of apoptosis during development. (b) CED-1 in engulfing cells can cause CED-3 caspase gradients in dividing cells, which leads to its unequal distribution in daughter cells. This results in differential apoptotic potential

Figure 3

Non-autonomous induction of apoptosis by other apoptotic cells. (a) During D. melanogaster development, apoptotic cells secrete Eiger to induce apoptosis of other cells through JNK-mediated pathways. Persistence of apoptotic cells can coax groups of cells that normally survive to undergo apoptosis. (b) Mammalian hair follicle cells undergo coordinated apoptosis through secretion of TNF-α by apoptotic cells. Treatment of follicle with a TNF-α neutralising antibody is sufficient to disrupt apoptosis

Figure 4

Non-autonomous regulation of germ cell apoptosis in C. elegans. CEP-1/p53 is activated in response to DNA damage and initiates apoptosis. Permissive signal from intestinal cells (KRI-1) is required for progression of apoptotic cascade in germ cells. In contrast, accumulation of neuronal HIF-1 results in suppression of the apoptosis cascade, probably through inhibition of CEP-1. Other somatic factors such as insulin/IGF-1 signalling and the RB protein LIN-35 also contribute to apoptosis