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Programmed cell death
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==Role in the development of the nervous system== [[File:Dying cells in the proliferative zone.jpg|thumb|right|Dying cells in the proliferate zone]] The initial expansion of the developing [[nervous system]] is counterbalanced by the removal of neurons and their processes.<ref name="Tau">{{cite journal|last=Tau|first=GZ|title=Normal development of brain circuits|journal=Neuropsychopharmacology|year=2009|volume=35|issue=1|pages=147β168|doi=10.1038/npp.2009.115|pmid=19794405|pmc=3055433}}</ref> During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).<ref name="Dekkers">{{cite journal|last=Dekkers|first=MP|title=Death of developing neurons: new insights and implications for connectivity|journal=Journal of Cell Biology|year=2013|volume=203|pages=385β393|doi=10.1083/jcb.201306136 |pmid=24217616|issue=3|pmc=3824005}}</ref> PCD in the nervous system was first recognized in 1896 by John Beard.<ref name="Oppenheim 1981">{{cite book|last=Oppenheim|first=RW|title=Neuronal cell death and some related regressive phenomena during neurogenesis: a selective historical review and progress report|year=1981|publisher=Oxford University Press|location=In Studies in Developmental Neurobiology: Essays in Honor of Viktor Hamburger|pages=74β133}}</ref> Since then several theories were proposed to understand its biological significance during [[neural development]].<ref name="Buss">{{cite journal|last=Buss|first=RR|title=Adaptive roles of programmed cell death during nervous system development|journal=Annual Review of Neuroscience|year=2006|volume=29|pages=1β35|doi=10.1146/annurev.neuro.29.051605.112800|pmid=16776578}}</ref> ===Role in neural development=== PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells.<ref name="Tau" /> One theory suggests that PCD is an adaptive mechanism to regulate the number of [[progenitor cells]]. In humans, PCD in progenitor cells starts at gestational week 7 and remains until the first trimester.<ref name="De la rosa">{{cite journal|last=De la Rosa|first=EJ|author2=De Pablo, F|title=Cell death in early neural development: beyond the neurotrophic theory|journal=Trends in Neurosciences|date=October 23, 2000|volume=23|issue=10|pages=454β458|doi=10.1016/s0166-2236(00)01628-3|pmid=11006461|s2cid=10493404}}</ref> This process of cell death has been identified in the germinal areas of the [[cerebral cortex]], [[cerebellum]], [[thalamus]], [[brainstem]], and [[spinal cord]] among other regions.<ref name="Buss" /> At gestational weeks 19β23, PCD is observed in post-mitotic cells.<ref name="Lossiand Merighi">{{cite journal|last=Lossi|first=L|author2=Merighi, A|title=In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS|journal=Progress in Neurobiology|date=April 2003|volume=69|issue=5|pages=287β312|doi=10.1016/s0301-0082(03)00051-0|pmid=12787572|s2cid=27052883}}</ref> The prevailing theory explaining this observation is the neurotrophic theory which states that PCD is required to optimize the connection between neurons and their afferent inputs and efferent targets.<ref name="Buss" /> Another theory proposes that developmental PCD in the nervous system occurs in order to correct for errors in neurons that have migrated ectopically, innervated incorrect targets, or have [[axons]] that have gone awry during path finding.<ref name="Finlay">{{cite journal|last=Finlay|first=BL|title=Control of cell number in the developing mammalian visual system|journal=Progress in Neurobiology|year=1989|volume=32|issue=3|pages=207β234|doi=10.1016/0301-0082(89)90017-8|pmid=2652194|s2cid=2788103}}</ref> It is possible that PCD during the development of the nervous system serves different functions determined by the developmental stage, cell type, and even species.<ref name="Buss" /> ===The neurotrophic theory=== The neurotrophic theory is the leading hypothesis used to explain the role of programmed cell death in the developing nervous system.<ref>{{Cite journal|last1=Yamaguchi|first1=Yoshifumi|last2=Miura|first2=Masayuki|date=2015-02-23|title=Programmed Cell Death in Neurodevelopment|journal=Developmental Cell|language=en|volume=32|issue=4|pages=478β490|doi=10.1016/j.devcel.2015.01.019|issn=1534-5807|pmid=25710534|doi-access=free}}</ref> It postulates that in order to ensure optimal innervation of targets, a surplus of neurons is first produced which then compete for limited quantities of protective [[neurotrophic factors]] and only a fraction survive while others die by programmed cell death.<ref name="De la rosa" /> Furthermore, the theory states that predetermined factors regulate the amount of neurons that survive and the size of the innervating neuronal population directly correlates to the influence of their target field.<ref name="Patterning PNS">{{cite book|last=Rubenstein|first=John|title=Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience|year=2013|publisher=Academic Press|isbn=978-0-12-397348-1|author2=Pasko Rakic|chapter=Regulation of Neuronal Survival by Neurotrophins in the Developing Peripheral Nervous System}}</ref> The underlying idea that target cells secrete attractive or inducing factors and that their [[growth cone]]s have a [[chemotactic]] sensitivity was first put forth by [[Santiago Ramon y Cajal]] in 1892.<ref name="Sotelo">{{cite book|last=Constantino|first=Sotelo|title=Changing Views of Cajal's Neuron |chapter=Chapter 2 the chemotactic hypothesis of Cajal: A century behind |series=Progress in Brain Research|year=2002|volume=136|pages=11β20|doi=10.1016/s0079-6123(02)36004-7|pmid=12143376|isbn=9780444508157}}</ref> Cajal presented the idea as an explanation for the "intelligent force" axons appear to take when finding their target but admitted that he had no empirical data.<ref name="Sotelo" /> The theory gained more attraction when experimental manipulation of axon targets yielded death of all innervating neurons. This developed the concept of target derived regulation which became the main tenet in the neurotrophic theory.<ref name="Oppenheim 2">{{cite journal|last=Oppenheim|first=Ronald|title=The neurotrophic theory and naturally occurring motorneuron death|journal=Trends in Neurosciences|year=1989|volume=12|issue=7|pages=252β255|doi=10.1016/0166-2236(89)90021-0|pmid=2475935|s2cid=3957751}}</ref><ref name="Death in developing">{{cite journal|last1=Dekkers|first1= MP|last2= Nikoletopoulou |first2=V|last3= Barde|first3= YA|title=Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity|journal=J Cell Biol|date=November 11, 2013|volume=203|issue=3|pages=385β393|doi=10.1083/jcb.201306136|pmid=24217616|pmc=3824005}}</ref> Experiments that further supported this theory led to the identification of the first neurotrophic factor, [[nerve growth factor]] (NGF).<ref name="Cowan">{{cite journal|last=Cowan|first=WN|title=Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor|journal=Annual Review of Neuroscience|year=2001|volume=24|pages=551β600|doi=10.1146/annurev.neuro.24.1.551|pmid=11283321|s2cid=6747529}}</ref> ===Peripheral versus central nervous system=== [[File:Programmed cell death in the peripheral and central nervous system.jpg|thumb|right|Cell death in the peripheral vs central nervous system]] Different mechanisms regulate PCD in the [[peripheral nervous system]] (PNS) versus the [[central nervous system]] (CNS). In the PNS, innervation of the target is proportional to the amount of the target-released neurotrophic factors NGF and [[NT3]].<ref name="Weltman">{{cite journal|last=Weltman|first=JK|title=The 1986 Nobel Prize for Physiology or Medicine awarded for discovery of growth factors: Rita Levi-Montalcini, M.D., and Stanley Cohen, Ph.D.|journal=New England Regional Allergy Proceedings|date=February 8, 1987|pmid=3302667|doi=10.2500/108854187779045385|volume=8|issue=1|pages=47β8}}</ref><ref name="Dekkers1">{{cite journal|last=Dekkers|first=M|title=Programmed Cell Death in Neuronal Development|journal=Science|date=April 5, 2013|volume=340|issue=6128|pages=39β41|doi=10.1126/science.1236152|pmid=23559240|bibcode=2013Sci...340...39D|s2cid=206548254}}</ref> Expression of neurotrophin receptors, [[TrkA]] and [[TrkC]], is sufficient to induce [[apoptosis]] in the absence of their [[ligands]].<ref name="Dekkers" /> Therefore, it is speculated that PCD in the PNS is dependent on the release of neurotrophic factors and thus follows the concept of the neurotrophic theory.{{cn|date=November 2024}} Programmed cell death in the CNS is not dependent on external [[growth factors]] but instead relies on intrinsically derived cues. In the [[neocortex]], a 4:1 ratio of excitatory to inhibitory [[interneurons]] is maintained by apoptotic machinery that appears to be independent of the environment.<ref name="Dekkers1" /> Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured [[in vitro]].<ref name="Southwell">{{cite journal|last=Southwell|first=D.G.|title=Intrinsically determined cell death of developing cortical interneurons|journal=Nature|date=November 2012|volume=491|issue=7422|pages=109β115|doi=10.1038/nature11523|pmid=23041929|pmc=3726009|bibcode=2012Natur.491..109S}}</ref> Transplanted cells died at the age of two weeks, the same age at which endogenous interneurons undergo apoptosis. Regardless of the size of the transplant, the fraction of cells undergoing apoptosis remained constant. Furthermore, disruption of [[TrkB]], a receptor for [[brain derived neurotrophic factor]] (Bdnf), did not affect cell death. It has also been shown that in mice null for the proapoptotic factor [[Bcl-2-associated X protein|Bax]] (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice.<ref name="Southwell" /> Together these findings indicate that programmed cell death in the CNS partly exploits Bax-mediated signaling and is independent of BDNF and the environment. Apoptotic mechanisms in the CNS are still not well understood, yet it is thought that apoptosis of interneurons is a self-autonomous process.{{cn|date=November 2024}} ===Nervous system development in its absence=== Programmed cell death can be reduced or eliminated in the developing nervous system by the targeted deletion of pro-apoptotic genes or by the overexpression of anti-apoptotic genes. The absence or reduction of PCD can cause serious anatomical malformations but can also result in minimal consequences depending on the gene targeted, neuronal population, and stage of development.<ref name="Buss" /> Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in [[caspase-3]] or [[caspase-9]] [[knockout mice]] which develop [[exencephaly]] in the [[forebrain]].<ref name="Kuida">{{cite journal|last=Kuida|first=K|title=Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9|journal=Cell|year=1998|volume=94|issue=3|pages=325β337|doi=10.1016/s0092-8674(00)81476-2|pmid=9708735|s2cid=8417446|doi-access=free}}</ref><ref name="Kuida decreased">{{cite journal|last=Kuida|first=K|title=Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice|journal=Nature|year=1996|volume=384|pages=368β372|doi=10.1038/384368a0|issue=6607|pmid=8934524|bibcode=1996Natur.384..368K|s2cid=4353931}}</ref> The brainstem, spinal cord, and peripheral ganglia of these mice develop normally, however, suggesting that the involvement of [[caspases]] in PCD during development depends on the brain region and cell type.<ref name="Oppenheim caspase">{{cite journal|last=Oppenheim|first=RW|title=Programmed cell death of developing mammalian neurons after genetic deletion of caspases|journal=Journal of Neuroscience|year=2001|volume=21|issue=13|pages=4752β4760|doi=10.1523/JNEUROSCI.21-13-04752.2001|pmid=11425902|pmc=6762357|doi-access=free}}</ref> Knockout or inhibition of apoptotic protease activating factor 1 ([[APAF1]]), also results in malformations and increased embryonic lethality.<ref name="Cecconi">{{cite journal|last=Cecconi|first=F|title=Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development|journal=Cell|year=1998|volume=94|issue=6|pages=727β737|doi=10.1016/s0092-8674(00)81732-8|pmid=9753320|doi-access=free}}</ref><ref name="Hao">{{cite journal|last=Hao|first=Z|title=Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis|journal=Cell|year=2005|volume=121|issue=4|pages=579β591|doi=10.1016/j.cell.2005.03.016|pmid=15907471|s2cid=4921039|doi-access=free}}</ref><ref name="Yoshida">{{cite journal|last=Yoshida|first=H|title=Apaf1 is required for mitochondrial pathways of apoptosis and brain development|journal=Cell|year=1998|volume=94|issue=6|pages=739β750|doi=10.1016/s0092-8674(00)81733-x|pmid=9753321|s2cid=1096066|doi-access=free}}</ref> Manipulation of apoptosis regulator proteins [[Bcl-2]] and Bax (overexpression of Bcl-2 or deletion of Bax) produces an increase in the number of neurons in certain regions of the nervous system such as the [[retina]], [[trigeminal nucleus]], cerebellum, and spinal cord.<ref name="Bonfanti">{{cite journal|last=Bonfanti|first=L|title=Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2|journal=Journal of Neuroscience|year=1996|volume=16|issue=13|pages=4186β4194|doi=10.1523/JNEUROSCI.16-13-04186.1996|pmid=8753880|pmc=6578989|doi-access=free}}</ref><ref name="Martinou">{{cite journal|last=Martinou|first=JC|title=Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia|journal=Neuron|year=1994|volume=13|issue=4|pages=1017β1030|doi=10.1016/0896-6273(94)90266-6|pmid=7946326|s2cid=25546670}}</ref><ref name="Zanjani">{{cite journal|last=Zanjani|first=HS|title=Increased cerebellar Purkinje cell numbers in mice overexpressing a human bcl-2 transgene|journal=Journal of Computational Neurology|year=1996|volume=374|issue=3|pages=332β341|doi=10.1002/(sici)1096-9861(19961021)374:3<332::aid-cne2>3.0.co;2-2|pmid=8906502|s2cid=32460867 }}</ref><ref name="Zup">{{cite journal|last=Zup|first=SL|title=Overexpression of bcl-2 reduces sex differences in neuron number in the brain and spinal cord|journal=Journal of Neuroscience|year=2003|volume=23|issue=6|pages=2357β2362|doi=10.1523/JNEUROSCI.23-06-02357.2003|pmid=12657695|pmc=6742046|doi-access=free}}</ref><ref name="Fan">{{cite journal|last=Fan|first=H|title=Elimination of Bax expression in mice increases cerebellar Purkinje cell numbers but not the number of granule cells|journal=Journal of Computational Neurology|year=2001|volume=436|issue=1|pages=82β91|doi=10.1002/cne.1055.abs|pmid=11413548}}</ref><ref name="Mosinger">{{cite journal|last=Mosinger|first=Ogilvie|title=Suppression of developmental retinal cell death but not of photoreceptor degeneration in Bax-deficient mice|journal=Investigative Ophthalmology & Visual Science|year=1998|volume=39|pages=1713β1720}}</ref><ref name="White">{{cite journal|last=White|first=FA|title=Widespread elimination of naturally occurring neuronal death in Bax-deficient mice|journal=Journal of Neuroscience|year=1998|volume=18|issue=4|pages=1428β1439|doi=10.1523/JNEUROSCI.18-04-01428.1998|pmid=9454852|pmc=6792725|doi-access=free}}</ref> However, PCD of neurons due to Bax deletion or Bcl-2 overexpression does not result in prominent morphological or behavioral abnormalities in mice. For example, mice overexpressing Bcl-2 have generally normal motor skills and vision and only show impairment in complex behaviors such as learning and anxiety.<ref name="Gianfranceschi">{{cite journal|last=Gianfranceschi|first=L|title=Behavioral visual acuity of wild type and bcl2 transgenic mouse|journal=Vision Research|year=1999|volume=39|issue=3|pages=569β574|doi=10.1016/s0042-6989(98)00169-2|pmid=10341985|s2cid=5544203|doi-access=free}}</ref><ref name="Rondi">{{cite journal|last=Rondi-Reig|first=L|title=To die or not to die, does it change the function? Behavior of transgenic mice reveals a role for developmental cell death|journal=Brain Research Bulletin|year=2002|volume=57|issue=1|pages=85β91|doi=10.1016/s0361-9230(01)00639-6|pmid=11827740|s2cid=35145189}}</ref><ref name="Rondi Transgenic Mice">{{cite journal|last=Rondi-Reig|first=L|title=Transgenic mice with neuronal overexpression of bcl-2 gene present navigation disabilities in a water task|journal=Neuroscience|year=2001|volume=104|issue=1|pages=207β215|doi=10.1016/s0306-4522(01)00050-1|pmid=11311543|s2cid=30817916}}</ref> The normal behavioral [[phenotypes]] of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.<ref name="Buss" /> ===Invertebrates and vertebrates=== [[File:A conserved apoptotic pathway in nematodes, mammals and fruitflies.jpg|thumb|right|A conserved apoptotic pathway in nematodes, mammals and fruitflies]] Learning about PCD in various species is essential in understanding the evolutionary basis and reason for apoptosis in development of the nervous system. During the development of the [[invertebrate]] nervous system, PCD plays different roles in different species.<ref>{{Cite journal|last1=Buss|first1=Robert R.|last2=Sun|first2=Woong|last3=Oppenheim|first3=Ronald W.|title=Adaptive Roles of Programmed Cell Death During Nervous System Development|date=2006-07-21|journal=Annual Review of Neuroscience|volume=29|issue=1|pages=1β35|doi=10.1146/annurev.neuro.29.051605.112800|pmid=16776578|issn=0147-006X}}</ref> The similarity of the asymmetric cell death mechanism in the [[nematode]] and the [[leech]] indicates that PCD may have an evolutionary significance in the development of the nervous system.<ref name="Sulston">{{cite journal|last=Sulston|first=JE|title=The Caenorhabditis elegans male: postembryonic development of nongonadal structures|journal=Developmental Biology|year=1980|volume=78|issue=2|pages=542β576|doi=10.1016/0012-1606(80)90352-8|pmid=7409314}}</ref> In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages.<ref name="Sulston1">{{cite journal|last=Sulston2|first=JE|title=The embryonic cell lineage of the nematode Caenorhabditis elegans|journal=Developmental Biology|year=1983|volume=100|pages=64β119|doi=10.1016/0012-1606(83)90201-4|pmid=6684600|issue=1}}</ref> Cell death in [[arthropods]] occurs first in the nervous system when [[ectoderm]] cells differentiate and one daughter cell becomes a [[neuroblast]] and the other undergoes apoptosis.<ref name="Doe">{{cite journal|last=Doe|first=Cq|title=Development and segmental differences in the pattern of neuronal precursor cells|journal=Journal of Developmental Biology|year=1985|volume=111|issue=1|pages=193β205|doi=10.1016/0012-1606(85)90445-2|pmid=4029506}}</ref> Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.<ref name="Giebultowicz">{{cite journal|last=Giebultowicz|first=JM|title=Sexual differentiation in the terminal ganglion of the moth Manduca sexta: role of sex-specific neuronal death|journal=Journal of Comparative Neurology|year=1984|volume=226|issue=1|pages=87β95|doi=10.1002/cne.902260107|pmid=6736297|s2cid=41793799}}</ref> In ''[[Drosophila]]'', PCD is essential in segmentation and specification during development.{{cn|date=November 2024}} In contrast to invertebrates, the mechanism of programmed cell death is found to be more conserved in [[vertebrates]]. Extensive studies performed on various vertebrates show that PCD of neurons and [[glia]] occurs in most parts of the nervous system during development. It has been observed before and during [[synaptogenesis]] in the central nervous system as well as the peripheral nervous system.<ref name="Buss" /> However, there are a few differences between vertebrate species. For example, [[mammals]] exhibit extensive arborization followed by PCD in the retina while birds do not.<ref name="Cook">{{cite journal|last=Cook|first=B|title=Developmental neuronal death is not a universal phenomenon among cell types in the chick embryo retina|journal=Journal of Comparative Neurology|year=1998|volume=396|issue=1|pages=12β19|doi=10.1002/(sici)1096-9861(19980622)396:1<12::aid-cne2>3.0.co;2-l|pmid=9623884|s2cid=25569721}}</ref> Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.<ref name="Buss" />
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