ReviewCell death in development: Signaling pathways and core mechanisms
Introduction
Cells die throughout the lifespan of multicellular organisms, and this physiologic cell death is critical for developmental plasticity and for organismal health [1]. In this review we describe the general functions of developmental cell death, focusing on nervous system development. The core cell death pathways that contribute to the majority of developmental cell death will be introduced, and the upstream regulation of these pathways in the context of the developing organism will be discussed.
Section snippets
The canonical pathway of cell death
Genes important for apoptosis are highly conserved from worms to man, and include the caspases, and their regulators (Fig. 1). The control of caspase activity is central to the regulation of developmental death. Caspase activity can be controlled by regulating both activation and inhibition. The relative importance of these two apoptosis control strategies varies between species and also between cell types, as well as in response to different apoptotic stimuli.
In Caenorhabditis elegans, the
Functions of cell death in development
Cell death is prevalent during the development of multicellular organisms. The majority of developmental cell death appears to be apoptotic [13], although alternative death pathways such as autophagy and necrosis may also contribute to the elimination of cells. The amount of cell death occurring during development can be underestimated, as phagocytes often eliminate dying cells within an hour of the initiation of death [14], [15], [16].
Examination of the distribution of dying cells and genetic
Regulation of developmental cell death
As described above, the central components of the apoptotic pathway have been extensively characterized. Less is known about how these components are activated in the correct cells at the correct time in development. Many pathways implicated in other developmental processes also regulate developmental cell death (summarized in Table 1).
Future directions
Apoptosis is a prevalent cell fate in during development. Pathways that regulate other developmental events can also regulate cell death. It is interesting to note that some regulatory pathways can activate or suppress cell death, depending on the developmental context. The temporal and tissue specific context cues that alter the cell death response will be an interesting area for future research. Until now, these studies have been difficult in vivo, given the rapidity of the apoptotic process
Acknowledgments
We would like to acknowledge funding from the MGH Fund for Medical Discovery (R.A.) and R01GM55568 and R01GM110477 (K.W.). Tatevik Sarkissian and Ritu Tomar provided important comments on the manuscript.
References (159)
- et al.
The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9
Cell
(1998) - et al.
The damage-responsive Drosophila gene sickle encodes a novel IAP binding protein similar to but distinct from reaper: grim, and hid
Curr Biol
(2002) - et al.
Drosophila sickle is a novel grim-reaper cell death activator
Curr Biol
(2002) - et al.
XIAP regulates caspase activity in degenerating axons
Cell Rep
(2013) - et al.
Inhibitor of apoptosis proteins (IAPs) as regulatory factors of hepatic apoptosis
Cell Signal
(2013) - et al.
Cell death and control of cell survival in the oligodendrocyte lineage
Cell
(1992) - et al.
Programmed cell death in animal development
Cell
(1997) - et al.
Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila
Cell
(2007) - et al.
Post-embryonic cell lineages of the nematode, Caenorhabditis elegans
Dev Biol
(1977) - et al.
The embryonic cell lineage of the nematode Caenorhabditis elegans
Dev Biol
(1983)
Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development
Cell
Differential requirement for caspase 9 in apoptotic pathways in vivo
Cell
Adult Apaf-1-deficient mice exhibit male infertility
Dev Biol
Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9
Cell
Apaf1 is required for mitochondrial pathways of apoptosis and brain development
Cell
Local apoptosis modulates early mammalian brain development through the elimination of morphogen-producing cells
Dev Cell
Temporal transcription factors and their targets schedule the end of neural proliferation in Drosophila
Cell
Spatial and temporal patterns of neurogenesis in the central nervous system of Drosophila melanogaster
Dev Biol
Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila
Curr Biol
Apoptosis ensures spacing pattern formation of Drosophila sensory organs
Curr Biol
Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway
Dev Biol
Temporal patterning of neuroblasts controls Notch-mediated cell survival through regulation of hid or reaper
Cell
Mek1/2 MAPK kinases are essential for Mammalian development: homeostasis, and Raf-induced hyperplasia
Dev Cell
Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye
Cell
Ras promotes cell survival in Drosophila by downregulating hid expression
Cell
The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling
Cell
Multiple mechanisms modulate distinct cellular susceptibilities toward apoptosis in the developing Drosophila eye
Dev Cell
Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase
Cell
Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila
Curr Biol
Apoptosis in Drosophila: neither fish nor fowl (nor man, nor worm)
J Cell Sci
Genetic control of programmed cell death in Drosophila
Science
grim: a novel cell death gene in Drosophila
Genes Dev
The head involution defective gene of Drosophila melanogaster functions in programmed cell death
Genes Dev
Regulation of apoptosis by inhibitors of apoptosis (IAPs)
Cells
Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis
J Cell Biol
Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning
Nat Commun
Cell deaths in normal vertebrate ontogeny
Biol Rev
Recognition and phagocytosis of cells undergoing apoptosis
Br Med Bull
Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion
Cold Spring Harb Perspect Biol
How death shapes life during development
Nat Rev Mol Cell Biol
Programmed cell death during animal development
Br Med Bull
The metamorphosis of Drosophila melanogaster: including an accurately timed account of the principal morphological changes
J Morphol
The postembryonic development of Drosophila
Steroid regulation of autophagic programmed cell death during development
Development
Caspases function in autophagic programmed cell death in Drosophila
Development
Programmed cell death in the developing limb
Int J Dev Biol
Genetic control of programmed cell death during animal development
Annu Rev Genet
Alternative cell death mechanisms in development and beyond
Genes Dev
Programmed cell death in the embryonic central nervous system of Drosophila melanogaster
Development
Adaptive roles of programmed cell death during nervous system development
Annu Rev Neurosci
Cited by (66)
Selective induction of programmed cell death using synthetic biology tools
2024, Seminars in Cell and Developmental BiologyThe antagonistic relationship between apoptosis and polyploidy in development and cancer
2024, Seminars in Cell and Developmental BiologyScaling dictates the decoder structure
2022, Science Bulletin