Editing Programmed cell death (section)

===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=325–337|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=368–372|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=4752–4760|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=727–737|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=579–591|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=739–750|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=4186–4194|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=1017–1030|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=332–341|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=2357–2362|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=82–91|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=1713–1720}}</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=1428–1439|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=569–574|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=85–91|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=207–215|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" />