Regulation of Neural Stem Cell Death (original) (raw)
Related papers
Programmed Cell Death in the Developing Nervous System
Brain Pathology, 1996
Virtually all cell populations in the vertebrate nervous system undergo massive "naturally-occurring" or "programmed" cell death (PCD) early i n development. Initially neurons and glia are overproduced followed by the demise of approximately one-half of the original cell population. In this review we highlight current hypotheses regarding how large-scale PCD contributes t o the construction of the developing nervous system. More germane t o the theme of this symposium, we emphasize that the survival of cells during PCD depends critically on their ability t o access "trophic" molecular signals derived primarily from interactions with other cells. Here we review the cell-cell interactions and molecular mechanisms that control neuronal and glial cell survival during PCD, and h o w the inability of such signals t o suppress PCD may contribute t o cell death in some diseases such as spinal muscular atrophy. Finally, by using neurotrophic factors (e.g. CNTF, GDNF) and genes that control the cell death cascade (e.g. Bcl-2) as examples, w e underscore the importance of studying the mechanisms that control neuronal and glial cell survival during normal development as a means of identifying molecules that prevent pathology-induced cell death. Ultimately this line of investigation could reveal effective strategies for arresting neuronal and glial cell death induced by injury, disease, and/or aging in humans.
Apoptosis in the mammalian nervous system: developmental and clinical implications
Biomedical Reviews, 2002
Among the many regulatory steps in brain development is the process of elimination of differentiating neurons at certain stages of maturation through an intrinsic suicide program now widely known as apoptosis. Apoptosis may thus describe a cell death pathway utilized by many developing cells in the nervous system, but may also be activated as a consequence of acute or chronic pathological impulses. Such pathological impulses may include brain injury, cerebral hypoxia-ischemia and the potentials of selected drugs such as N-methyl D-aspartate (NMDA) receptor antagonists, GABA mimetics and ethanol. In recent years, there has been a great interest in mechanisms of cell death in the nervous system and apoptotic cell death has been implicated in many neurodegenerative diseases such as Alzheimer's disease, amiotrophic lateral sclerosis, Parkinson's disease and other central and peripheral nervous system disorders. Recent findings have evaluated the contribution of programmed cell death and specific gene products involved in each of these cases. A deeper understanding of these processes may lead to the discovery of strategies for slowing, reducing or arresting neuronal and glial cell death induced by injury, aging or disease.
Mechanisms of programmed cell death in the developing brain
2000
C ELL DEATH has long been recognized to occur in most neuronal populations during normal development of the vertebrate nervous system (reviewed in Ref. 1). Traditionally, the investigation of neural death in development focused on the role of target-derived survival factors such as NGF and related neurotrophins (see Ref. 2 for a review). However, in the past few years, the genetic analysis of programmed cell death in the nematode Caenorhabditis elegans has inspired new approaches to study this phenomenon (see Box 1 for the developmental functions of programmed cell death). It is through such gene-targeting studies that recent insights into the molecular regulation of mammalian programmed cell death have been obtained.
In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS
Apoptosis has been recognized to be an essential process during neural development. It is generally assumed that about half of the neurons produced during neurogenesis die before completion of the central nervous system (CNS) maturation, and this process affects nearly all classes of neurons. In this review, we discuss the experimental data in vivo on naturally occurring neuronal death in normal, transgenic and mutant animals, with special attention to the cerebellum as a study model. The emerging picture is that of a dual wave of apoptotic cell death affecting central neurons at different stages of their life. The first wave consists of an early neuronal death of proliferating precursors and young postmitotic neuroblasts, and appears to be closely linked to cell cycle regulation. The second wave affects postmitotic neurons at later stages, and is much better understood in functional terms, mainly on the basis of the neurotrophic concept in its broader definition. The molecular machinery of late apoptotic death of postmitotic neurons more commonly follows the mitochondrial pathway of intracellular signal transduction, but the death receptor pathway may also be involved.
A Perspective on Neuronal Cell Death Signaling and Neurodegeneration
Molecular Neurobiology, 2010
Loss of neurons is typically the readout used for studies of neuropathological conditions ranging from stroke and traumatic brain injury to adult-onset neurodegenerative diseases such as Alzheimer's and Parkinson's[1]. One result is that studies of neurodegenerative disease often become descriptions of progressive neuronal cell death, and many therapeutic strategies focus on preventing cell death [2, 3]. Unfortunately, successes in reducing or preventing neuronal cell death have not translated to effective treatments for any neurodegenerative disease [4-6]. The problem is that neurodegenerative diseases are not caused by cell death signaling pathways. Although apoptotic pathways will eventually be activated and neurons lost as the disease progresses, the clinical symptoms of neurodegenerative diseases reflect abnormalities in synaptic function and the loss of synaptic connections, rather than the loss of neurons. Conflating the shared molecular mechanisms of cell death with unique disease-specific pathogenic mechanisms of neurodegeneration may be interfering with the search for effective therapies. Although the final common steps in cell death pathways (i.e., nuclear fragmentation, etc.) are shared between neuronal and nonneuronal cells[7, 8], the sequence of events leading to cell death in neurons may include steps not found in nonneuronal cells[9]. Neuron-specific features may involve an extended period of time, often months or years, in contrast with the rapid progression of apoptosis observed in non-neuronal cells[10]. These initial neuronspecific steps manifest as a loss of synaptic function, a process initiated at a considerable distance from the neuronal perikaryon. Complicating the situation further, components of cell death signaling pathways can play roles in neurons unrelated to cell death, such as regulating aspects of synaptic function and plasticity[11-13].
Developmental Cell Death in the Cerebral Cortex
Annual Review of Cell and Developmental Biology, 2019
In spite of the high metabolic cost of cellular production, the brain contains only a fraction of the neurons generated during embryonic development. In the rodent cerebral cortex, a first wave of programmed cell death surges at embryonic stages and affects primarily progenitor cells. A second, larger wave unfolds during early postnatal development and ultimately determines the final number of cortical neurons. Programmed cell death in the developing cortex is particularly dependent on neuronal activity and unfolds in a cell-specific manner with precise temporal control. Pyramidal cells and interneurons adjust their numbers in sync, which is likely crucial for the establishment of balanced networks of excitatory and inhibitory neurons. In contrast, several other neuronal populations are almost completely eliminated through apoptosis during the first two weeks of postnatal development, highlighting the importance of programmed cell death in sculpting the mature cerebral cortex.
Coordinated expression of cell death genes regulates neuroblast apoptosis
Development, 2011
Properly regulated apoptosis in the developing central nervous system is crucial for normal morphogenesis and homeostasis. In Drosophila, a subset of neural stem cells, or neuroblasts, undergo apoptosis during embryogenesis. Of the 30 neuroblasts initially present in each abdominal hemisegment of the embryonic ventral nerve cord, only three survive into larval life, and these undergo apoptosis in the larvae. Here, we use loss-of-function analysis to demonstrate that neuroblast apoptosis during embryogenesis requires the coordinated expression of the cell death genes grim and reaper, and possibly sickle. These genes are clustered in a 140 kb region of the third chromosome and show overlapping patterns of expression. We show that expression of grim, reaper and sickle in embryonic neuroblasts is controlled by a common regulatory region located between reaper and grim. In the absence of grim and reaper, many neuroblasts survive the embryonic period of cell death and the ventral nerve cord becomes massively hypertrophic. Deletion of grim alone blocks the death of neuroblasts in the larvae. The overlapping activity of these multiple cell death genes suggests that the coordinated regulation of their expression provides flexibility in this crucial developmental process.
2002
Among the many regulatory steps in brain development is the process of elimination of differentiating neurons at certain stages of maturation through an intrinsic suicide program now widely known as apoptosis. Apoptosis may thus describe a cell death pathway utilized by many developing cells in the nervous system, but may also be activated as a consequence of acute or chronic pathological impulses. Such pathological impulses may include brain injury, cerebral hypoxia-ischemia and the potentials of selected drugs such as N-methyl D-aspartate (NMDA) receptor antagonists, GABA mimetics and ethanol. In recent years, there has been a great interest in mechanisms of cell death in the nervous system and apoptotic cell death has been implicated in many neurodegenerative diseases such as Alzheimer’s disease, amiotrophic lateral sclerosis, Parkinson’s disease and other central and peripheral nervous system disorders. Recent findings have evaluated the contribution of programmed cell death and...