Editing Programmed cell death (section)

===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=478–490|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=11–20|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=252–255|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=385–393|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=551–600|doi=10.1146/annurev.neuro.24.1.551|pmid=11283321|s2cid=6747529}}</ref>