Editing Axon (section)

==Development and growth==
===Development===
The development of the axon to its target, is one of the six major stages in the overall [[development of the nervous system]].<ref name="Wolpert">{{cite book|last1=Wolpert|first1=Lewis|title=Principles of development|date=2015|isbn=978-0-19-967814-3|pages=520–524|publisher=Oxford University Press |edition=5th}}</ref> Studies done on cultured [[hippocampus|hippocampal]] neurons suggest that neurons initially produce multiple [[neurite]]s that are equivalent, yet only one of these neurites is destined to become the axon.<ref>{{cite journal | vauthors = Fletcher TL, Banker GA | title = The establishment of polarity by hippocampal neurons: the relationship between the stage of a cell's development in situ and its subsequent development in culture | journal = Developmental Biology | volume = 136 | issue = 2 | pages = 446–54 | date = December 1989 | pmid = 2583372 | doi = 10.1016/0012-1606(89)90269-8 }}</ref> It is unclear whether axon specification precedes axon elongation or vice versa,<ref>{{cite journal | vauthors = Jiang H, Rao Y | title = Axon formation: fate versus growth | journal = Nature Neuroscience | volume = 8 | issue = 5 | pages = 544–6 | date = May 2005 | pmid = 15856056 | doi = 10.1038/nn0505-544 | s2cid = 27728967 }}</ref> although recent evidence points to the latter. If an axon that is not fully developed is cut, the polarity can change and other neurites can potentially become the axon. This alteration of polarity only occurs when the axon is cut at least 10 μm shorter than the other neurites. After the incision is made, the longest neurite will become the future axon and all the other neurites, including the original axon, will turn into dendrites.<ref>{{cite journal | vauthors = Goslin K, Banker G | title = Experimental observations on the development of polarity by hippocampal neurons in culture | journal = The Journal of Cell Biology | volume = 108 | issue = 4 | pages = 1507–16 | date = April 1989 | pmid = 2925793 | pmc = 2115496 | doi = 10.1083/jcb.108.4.1507 }}</ref> Imposing an external force on a neurite, causing it to elongate, will make it become an axon.<ref>{{cite journal | vauthors = Lamoureux P, Ruthel G, Buxbaum RE, Heidemann SR | title = Mechanical tension can specify axonal fate in hippocampal neurons | journal = The Journal of Cell Biology | volume = 159 | issue = 3 | pages = 499–508 | date = November 2002 | pmid = 12417580 | pmc = 2173080 | doi = 10.1083/jcb.200207174 }}</ref> Nonetheless, axonal development is achieved through a complex interplay between extracellular signaling, intracellular signaling and [[cytoskeleton|cytoskeletal]] dynamics.

====Extracellular signaling====
The extracellular signals that propagate through the [[extracellular matrix]] surrounding neurons play a prominent role in axonal development.<ref name="pmid17311006">{{cite journal | vauthors = Arimura N, Kaibuchi K | title = Neuronal polarity: from extracellular signals to intracellular mechanisms | journal = Nature Reviews. Neuroscience | volume = 8 | issue = 3 | pages = 194–205 | date = March 2007 | pmid = 17311006 | doi = 10.1038/nrn2056 | s2cid = 15556921 }}</ref> These signaling molecules include proteins, [[neurotrophic factors]], and extracellular matrix and adhesion molecules.
[[Netrin]] (also known as UNC-6) a secreted protein, functions in axon formation. When the [[UNC-5]] netrin receptor is mutated, several neurites are irregularly projected out of neurons and finally a single axon is extended anteriorly.<ref name="A">[[Neuroglia]] and [[pioneer neuron]]s express UNC-6 to provide global and local netrin cues for guiding migrations in [[Caenorhabditis elegans|''C. elegans'']]</ref><ref>{{cite journal | vauthors = Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell TM, Tessier-Lavigne M | title = The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6 | journal = Cell | volume = 78 | issue = 3 | pages = 409–24 | date = August 1994 | pmid = 8062384 | doi = 10.1016/0092-8674(94)90420-0 | s2cid = 22666205 }}</ref><ref>{{cite journal | vauthors = Hong K, Hinck L, Nishiyama M, Poo MM, Tessier-Lavigne M, Stein E | title = A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion | journal = Cell | volume = 97 | issue = 7 | pages = 927–41 | date = June 1999 | pmid = 10399920 | doi = 10.1016/S0092-8674(00)80804-1 | s2cid = 18043414 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hedgecock EM, Culotti JG, Hall DH | title = The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans | journal = Neuron | volume = 4 | issue = 1 | pages = 61–85 | date = January 1990 | pmid = 2310575 | doi = 10.1016/0896-6273(90)90444-K | s2cid = 23974242 }}</ref> The neurotrophic factors{{Snd}}[[nerve growth factor]] (NGF), [[brain-derived neurotrophic factor]] (BDNF) and [[neurotrophin-3]] (NTF3) are also involved in axon development and bind to [[Trk receptor]]s.<ref>{{cite journal | vauthors = Huang EJ, Reichardt LF | s2cid = 10217268 | title = Trk receptors: roles in neuronal signal transduction | journal = Annual Review of Biochemistry | volume = 72 | pages = 609–42 | year = 2003 | pmid = 12676795 | doi = 10.1146/annurev.biochem.72.121801.161629 }}</ref>

The [[ganglioside]]-converting enzyme plasma membrane ganglioside [[sialidase]] (PMGS), which is involved in the activation of [[TrkA]] at the tip of neutrites, is required for the elongation of axons. PMGS asymmetrically distributes to the tip of the neurite that is destined to become the future axon.<ref name="pmid15834419">{{cite journal | vauthors = Da Silva JS, Hasegawa T, Miyagi T, Dotti CG, Abad-Rodriguez J | title = Asymmetric membrane ganglioside sialidase activity specifies axonal fate | journal = Nature Neuroscience | volume = 8 | issue = 5 | pages = 606–15 | date = May 2005 | pmid = 15834419 | doi = 10.1038/nn1442 | s2cid = 25227765 }}</ref>

====Intracellular signaling====
During axonal development, the activity of [[PI3K]] is increased at the tip of destined axon. Disrupting the activity of PI3K inhibits axonal development. Activation of PI3K results in the production of [[phosphatidylinositol (3,4,5)-trisphosphate]] (PtdIns) which can cause significant elongation of a neurite, converting it into an axon. As such, the overexpression of [[phosphatase]]s that dephosphorylate PtdIns leads into the failure of polarization.<ref name="pmid17311006" />

====Cytoskeletal dynamics====
The neurite with the lowest [[actin]] filament content will become the axon. PGMS concentration and [[Actin#F-Actin|f-actin]] content are inversely correlated; when PGMS becomes enriched at the tip of a neurite, its f-actin content is substantially decreased.<ref name="pmid15834419" /> In addition, exposure to actin-depolimerizing drugs and toxin B (which inactivates [[Rho family of GTPases|Rho-signaling]]) causes the formation of multiple axons. Consequently, the interruption of the actin network in a growth cone will promote its neurite to become the axon.<ref>{{cite journal | vauthors = Bradke F, Dotti CG | title = The role of local actin instability in axon formation | journal = Science | volume = 283 | issue = 5409 | pages = 1931–4 | date = March 1999 | pmid = 10082468 | doi = 10.1126/science.283.5409.1931 | bibcode = 1999Sci...283.1931B }}</ref>

===Growth===
{{Main|Axon guidance}}
[[File:Axon two photon.jpg|thumb|right|upright|Axon of nine-day-old mouse with growth cone visible]]
Growing axons move through their environment via the [[growth cone]], which is at the tip of the axon. The growth cone has a broad sheet-like extension called a [[lamellipodium]] which contain protrusions called [[filopodia]]. The filopodia are the mechanism by which the entire process adheres to surfaces and explores the surrounding environment. Actin plays a major role in the mobility of this system. Environments with high levels of [[cell adhesion molecule]]s (CAMs) create an ideal environment for axonal growth. This seems to provide a "sticky" surface for axons to grow along. Examples of CAMs specific to neural systems include [[Neural cell adhesion molecule|N-CAM]], [[Contactin 2|TAG-1]]{{Snd}}an axonal [[glycoprotein]]<ref name="Furley">{{cite journal | vauthors = Furley AJ, Morton SB, Manalo D, Karagogeos D, Dodd J, Jessell TM | title = The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity | journal = Cell | volume = 61 | issue = 1 | pages = 157–70 | date = April 1990 | pmid = 2317872 | doi = 10.1016/0092-8674(90)90223-2 | s2cid = 28813676 | doi-access = free }}</ref>{{Snd}}and [[Myelin-associated glycoprotein|MAG]], all of which are part of the [[immunoglobulin]] superfamily. Another set of molecules called [[extracellular matrix]]-[[cell adhesion molecule|adhesion molecule]]s also provide a sticky substrate for axons to grow along. Examples of these molecules include [[laminin]], [[fibronectin]], [[tenascin]], and [[perlecan]]. Some of these are surface bound to cells and thus act as short range attractants or repellents. Others are difusible ligands and thus can have long range effects.

Cells called [[guidepost cells]] assist in the [[axon guidance|guidance]] of neuronal axon growth. These cells that help [[axon guidance]], are typically other neurons that are sometimes immature. When the axon has completed its growth at its connection to the target, the diameter of the axon can increase by up to five times, depending on the [[Nerve conduction velocity|speed of conduction]] required.<ref name="Alberts">{{cite book |last1=Alberts |first1=Bruce |title=Molecular biology of the cell |date=2015 |isbn=9780815344643 |page=947 |edition=Sixth}}</ref>

It has also been discovered through research that if the axons of a neuron were damaged, as long as the soma (the cell body of a neuron) is not damaged, the axons would regenerate and remake the synaptic connections with neurons with the help of [[guidepost cells]]. This is also referred to as [[neuroregeneration]].<ref>{{cite journal | vauthors = Kunik D, Dion C, Ozaki T, Levin LA, Costantino S | title = Laser-based single-axon transection for high-content axon injury and regeneration studies | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e26832 | year = 2011 | pmid = 22073205 | pmc = 3206876 | doi = 10.1371/journal.pone.0026832 | bibcode = 2011PLoSO...626832K | doi-access = free }}</ref>

[[Reticulon 4|Nogo-A]] is a type of neurite outgrowth inhibitory component that is present in the central nervous system myelin membranes (found in an axon). It has a crucial role in restricting axonal regeneration in adult mammalian central nervous system. In recent studies, if Nogo-A is blocked and neutralized, it is possible to induce long-distance axonal regeneration which leads to enhancement of functional recovery in rats and mouse spinal cord. This has yet to be done on humans.<ref>{{cite journal | vauthors = Schwab ME | title = Nogo and axon regeneration | journal = Current Opinion in Neurobiology | volume = 14 | issue = 1 | pages = 118–24 | date = February 2004 | pmid = 15018947 | doi = 10.1016/j.conb.2004.01.004 | s2cid = 9672315 }}</ref> A recent study has also found that [[macrophage]]s activated through a specific inflammatory pathway activated by the [[CLEC7A|Dectin-1]] receptor are capable of promoting axon recovery, also however causing [[neurotoxicity]] in the neuron.<ref>{{cite journal | vauthors = Gensel JC, Nakamura S, Guan Z, van Rooijen N, Ankeny DP, Popovich PG | title = Macrophages promote axon regeneration with concurrent neurotoxicity | journal = The Journal of Neuroscience | volume = 29 | issue = 12 | pages = 3956–68 | date = March 2009 | pmid = 19321792 | pmc = 2693768 | doi = 10.1523/JNEUROSCI.3992-08.2009 }}</ref>

===Length regulation===
Axons vary largely in length from a few micrometers up to meters in some animals. This emphasizes that there must be a cellular length regulation mechanism allowing the neurons both to sense the length of their axons and to control their growth accordingly. It was discovered that [[motor proteins]] play an important role in regulating the length of axons.<ref>{{cite journal | vauthors = Myers KA, Baas PW | title = Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array | journal = The Journal of Cell Biology | volume = 178 | issue = 6 | pages = 1081–91 | date = September 2007 | pmid = 17846176 | pmc = 2064629 | doi = 10.1083/jcb.200702074 }}</ref> Based on this observation, researchers developed an explicit model for axonal growth describing how motor proteins could affect the axon length on the molecular level.<ref>{{cite journal | vauthors = Rishal I, Kam N, Perry RB, Shinder V, Fisher EM, Schiavo G, Fainzilber M | title = A motor-driven mechanism for cell-length sensing | journal = Cell Reports | volume = 1 | issue = 6 | pages = 608–16 | date = June 2012 | pmid = 22773964 | pmc = 3389498 | doi = 10.1016/j.celrep.2012.05.013 }}</ref><ref>{{cite journal | vauthors = Karamched BR, Bressloff PC | title = Delayed feedback model of axonal length sensing | journal = Biophysical Journal | volume = 108 | issue = 9 | pages = 2408–19 | date = May 2015 | pmid = 25954897 | pmc = 4423051 | doi = 10.1016/j.bpj.2015.03.055 | bibcode = 2015BpJ...108.2408K }}</ref><ref>{{cite journal | vauthors = Bressloff PC, Karamched BR | title = A frequency-dependent decoding mechanism for axonal length sensing | journal = Frontiers in Cellular Neuroscience | volume = 9 | pages = 281 | year = 2015 | pmid = 26257607 | pmc = 4508512 | doi = 10.3389/fncel.2015.00281 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Folz F, Wettmann L, [[Giovanna Morigi|Morigi G]], Kruse K | title = Sound of an axon's growth | journal = Physical Review E | volume = 99 | issue = 5–1 | pages = 050401 | date = May 2019 | pmid = 31212501 | doi = 10.1103/PhysRevE.99.050401 | arxiv = 1807.04799 | bibcode = 2019PhRvE..99e0401F | s2cid = 118682719 }}</ref> These studies suggest that motor proteins carry signaling molecules from the soma to the growth cone and vice versa whose concentration oscillates in time with a length-dependent frequency.