Cell death in animal development

Abstract

Cell death is an important facet of animal development. In some developing tissues, death is the ultimate fate of over 80% of generated cells. Although recent studies have delineated a bewildering number of cell death mechanisms, most have only been observed in pathological contexts, and only a small number drive normal development. This Primer outlines the important roles, different types and molecular players regulating developmental cell death, and discusses recent findings with which the field currently grapples. We also clarify terminology, to distinguish between developmental cell death mechanisms, for which there is evidence for evolutionary selection, and cell death that follows genetic, chemical or physical injury. Finally, we suggest how advances in understanding developmental cell death may provide insights into the molecular basis of developmental abnormalities and pathological cell death in disease.

Keywords: Apoptosis; Caspase; Cell compartment elimination; Cell death; LCD; Linker cell-type death; Non-apoptotic cell death; Pathological cell death.

Fig. 1.

Conserved apoptotic pathways. (A-C) Apoptotic cascades are initiated at the mitochondrion in C. elegans (A) and Drosophila (B) and also at the cell surface in mammals (C), resulting in caspase activation. Based on Fuchs and Steller (2011).

Fig. 2.

Regulation of linker cell-type death in C. elegans. (A) Electron micrograph of a C. elegans apoptotic cell. (B) Electron micrograph of a C. elegans linker cell dying by LCD. nl, nucleolus. Arrows, nuclear invaginations/crenellations. Asterisks, swollen organelles. (C) Pathway for LCD in C. elegans. LCD in worms is subject to both cell-autonomous transcriptional control and non-autonomous control through multiple control pathways. Death onset is controlled by two opposing Wnt pathways (blue). The Wnt ligand LIN-44 acts non-autonomously in conjunction with the Frizzled receptors MIG-1 and CFZ-2, the Nemo-like kinase LIT-1 and the β-catenin WRM-1 in the linker cell to possibly prevent premature death. A second Wnt pathway inhibits the LIN-44/Wnt pathway. Here, EGL-20/Wnt acts non-autonomously, and LIN-17/Frizzled and MOM-5/Frizzled act in the linker cell with MIG-5/Disheveled and BAR-1/β-catenin, promoting death. This second pathway is likely controlled by two additional transcription factors, NOB-1/Hox and the EOR-1/-2/PLZF complex. In a parallel pathway (green), death is promoted by TIR-1, the C. elegans ortholog of mammalian Sarm, which activates the MAPKK protein SEK-1, which in turn may promote expression of the polyglutamine-repeat protein PQN-41 in the linker cell. The zinc-finger protein LIN-29 (red), which regulates developmental timing, and the nuclear hormone receptor NHR-67 (pink) appear to act independently of and in parallel with the Wnt and MAPKK pathways to promote death. In addition, HSF-1 may transcriptionally activate components of the ubiquitin proteasome system (purple).The pro-death function of HSF-1 (LC) competes with the pro-survival function (HS). Adapted from Kutscher and Shaham (2017). Scale bars: 0.5 μm.

Fig. 3.

Neurite-specific elimination. (A) Cell process fragmentation. (B) Cell process retraction, or ‘dying back’. (C) Wallerian degeneration: following axon severing (red arrow) the cell body remains intact while the axon fragments.

Fig. 4.

Compartmentalized cell elimination. (A-D) Images of a dying C. elegans tail-spike cell at different stages of death. (A) An intact tail-spike cell with a soma and long process. The proximal process segment (p) undergoes localized beading and fragmentation (B) and is eliminated before the soma (s) and distal process (d) (C). The soma rounds (B,C). The distal segment undergoes bidirectional retraction into a compact structure (C,D) and is eventually engulfed and removed. The entire cell is eliminated in ∼150 min. The caspase CED-3 acts independently in each compartment. Adapted from Ghose et al. (2018). TSCpro, tail-spike cell promoter; myrGFP, myristoylated green fluorescent protein (GFP).