Apoptosis and necrosis are the two major modes of cell death, the molecular mechanisms of which have been extensively studied. Although initially thought to constitute mutually exclusive cellular states, recent findings reveal cellular contexts that require a balanced interplay between these two modes of cellular demise. Several death initiator and effector molecules, signaling pathways and subcellular sites have been identified as key mediators in both processes, either by constituting common modules or alternatively by functioning as a switch allowing cells to decide which route to take, depending on the specific situation. Importantly, autophagy, which is a predominantly cytoprotective process, has been linked to both types of cell death, serving either a pro-survival or pro-death function. Here we review the recent literature that highlights the intricate interplay between apoptosis, necrosis and autophagy, focusing on the relevance and impact of this crosstalk in normal development and in pathology. This article is part of a Special Section entitled: Cell Death Pathways.
Topoisomerases are essential for DNA replication in dividing cells, but their genomic targets and function in postmitotic cells remain poorly understood. Here we show that a switch in the expression from Topoisomerases IIα (Top2α) to IIβ (Top2β) occurs during neuronal differentiation in vitro and in vivo. Genome-scale location analysis in stem cell-derived postmitotic neurons reveals Top2β binding to chromosomal sites that are methylated at lysine 4 of histone H3, a feature of regulatory regions. Indeed Top2β-bound sites are preferentially promoters and become targets during the transition from neuronal progenitors to neurons, at a time when cells exit the cell cycle. Absence of Top2β protein or its activity leads to changes in transcription and chromatin accessibility at many target genes. Top2β deficiency does not impair stem cell properties and early steps of neuronal differentiation but causes premature death of postmitotic neurons. This neuronal degeneration is caused by up-regulation of Ngfr p75, a gene bound and repressed by Top2β. These findings suggest a chromatin-based targeting of Top2β to regulatory regions in the genome to govern the transcriptional program associated with neuronal differentiation and longevity.epigenetic regulation | neurogenesis | gene expression | genomewide assays T opoisomerases are essential for solving topological problems arising from DNA-templated processes such as replication, transcription, recombination, chromatin remodeling, chromosome condensation, and segregation (1-5). The type I subfamily of topoisomerases achieves this task by passing one strand of the DNA through a break in the opposing strand; proteins in the type II subfamily pass a region of duplex strands from the same or a different molecule through a double-stranded gap generated in DNA (1-5). Mammalian cells encode two isozymes of type II enzymes that have highly homologous N-terminal ATPase and central core domains but differ at their C-termini (6). These two isozymes, Topoisomerases IIα (Top2α) and IIβ (Top2β), have almost identical enzymatic properties in vitro (7, 8); however, their expression patterns are dissimilar. Top2α is the main isoform expressed in proliferating cells, shows high expression in S/G2/M phases of the cell cycle, and plays important roles in DNA replication and chromosome condensation/segregation during the cell cycle (9-12).The cellular functions of Top2β are much less well understood. It is expressed in all mammalian cells throughout the cell cycle but is up-regulated robustly when cells reach a postmitotic state of terminal differentiation (13-15). For example, the postmitotic granule cells in the external germinal layer of the developing rat cerebellum show a transition from Top2α to Top2β (14), and blocking Top2β catalytic activity affects the expression of about one third of genes induced during differentiation of rat cerebellar granule neurons (16). Genetic deletion of Top2b in mice causes neural defects including aberrant axonal elongation and branching and perinatal death e...
Neurons of the peripheral nervous system have long been known to require survival factors to prevent their death during development. But why they selectively become dependent on secretory molecules has remained a mystery, as is the observation that in the central nervous system, most neurons do not show this dependency. Using engineered embryonic stem cells, we show here that the neurotrophin receptors TrkA and TrkC (tropomyosin receptor kinase A and C, also known as Ntrk1 and Ntrk3, respectively) instruct developing neurons to die, both in vitro and in vivo. By contrast, TrkB (also known as Ntrk2), a closely related receptor primarily expressed in the central nervous system, does not. These results indicate that TrkA and TrkC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic-factor-dependent for survival. We suggest that the expansion of the Trk gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control.
Autophagy is crucial for neuronal integrity. Loss of key autophagic components leads to progressive neurodegeneration and structural defects in pre- and postsynaptic morphologies. However, the molecular mechanisms regulating autophagy in the brain remain elusive. Similarly, while it is widely accepted that protein turnover is required for synaptic plasticity, the contribution of autophagy to the degradation of synaptic proteins is unknown. Here, we report that BDNF signaling via the tropomyosin receptor kinase B (TrkB) and the phosphatidylinositol-3' kinase (PI3K)/Akt pathway suppresses autophagy in vivo. In addition, we demonstrate that suppression of autophagy is required for BDNF-induced synaptic plasticity and for memory enhancement under conditions of nutritional stress. Finally, we identify three key remodelers of postsynaptic densities as cargo of autophagy. Our results establish autophagy as a pivotal component of BDNF signaling, which is essential for BDNF-induced synaptic plasticity. This molecular mechanism underlies behavioral adaptations that increase fitness in times of scarcity.
Neurons are highly specialized postmitotic cells that depend on dynamic cellular processes for their proper function.These include among others, neuronal growth and maturation, axonal migration, synapse formation and elimination, all requiring continuous protein synthesis and degradation. Therefore quality-control processes in neurons are directly linked to their physiology. Autophagy is a tightly regulated cellular degradation pathway by which defective or superfluouscytosolic proteins, organelles and other cellular constituents are sequestered in autophagosomes and delivered to lysosomes for degradation. Here we present emerging evidence indicating that constitutive autophagic fluxin neurons has essential roles in key neuronal processes under physiological conditions.Moreover, we discuss how perturbations of the autophagic pathway may underlie diverse pathological phenotypes in neurons associated with neurodevelopmental and neurodegenerative diseases.
Heat stroke is a life-threatening condition, characterized by catastrophic collapse of thermoregulation and extreme hyperthermia. In recent years, intensification of heat waves has caused a surge of heat-stroke fatalities. The mechanisms underlying heat-related pathology are poorly understood. Here we show that heat stroke triggers pervasive necrotic cell death and neurodegeneration in Caenorhabditis elegans. Preconditioning of animals at a mildly elevated temperature strongly protects from heat-induced necrosis. The heat-shock transcription factor HSF-1 and the small heat-shock protein HSP-16.1 mediate cytoprotection by preconditioning. HSP-16.1 localizes to the Golgi, where it functions with the Ca(2+)- and Mn(2+)-transporting ATPase PMR-1 to maintain Ca(2+) homeostasis under heat stroke. Preconditioning also suppresses cell death inflicted by diverse insults, and protects mammalian neurons from heat cytotoxicity. These findings reveal an evolutionarily conserved mechanism that defends against diverse necrotic stimuli, and may be relevant to heat stroke and other pathological conditions involving necrosis in humans.
The concept that target tissues determine the survival of neurons has inspired much of the thinking on neuronal development in vertebrates, not least because it is supported by decades of research on nerve growth factor (NGF) in the peripheral nervous system (PNS). Recent discoveries now help to understand why only some developing neurons selectively depend on NGF. They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS. Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.
Here we show a novel function for Retinoblastoma family member, p107 in controlling stem cell expansion in the mammalian brain. Adult p107-null mice had elevated numbers of proliferating progenitor cells in their lateral ventricles. In vitro neurosphere assays revealed striking increases in the number of neurosphere forming cells from p107−/− brains that exhibited enhanced capacity for self-renewal. An expanded stem cell population in p107-deficient mice was shown in vivo by (a) increased numbers of slowly cycling cells in the lateral ventricles; and (b) accelerated rates of neural precursor repopulation after progenitor ablation. Notch1 was up-regulated in p107−/− neurospheres in vitro and brains in vivo. Chromatin immunoprecipitation and p107 overexpression suggest that p107 may modulate the Notch1 pathway. These results demonstrate a novel function for p107 that is distinct from Rb, which is to negatively regulate the number of neural stem cells in the developing and adult brain.
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