Editing Neurulation (section)

=== Primary neural induction ===
The concept of induction originated in work by Pandor in 1817.<ref>Tiedemann, H. Chemical approach to the inducing agents. In: O. Nakamura & S. Toivonen (eds.), Organizer - A Milestone of a Half- Century from Spemann, Amsterdam: Elsevier/North Holland Biomedical Press, p. 91- 117. 1978</ref> The first experiments proving induction were attributed by [[Viktor Hamburger]]<ref>Hamburger, V.. The Heritage of Experimental Embryology: Hans Spemann and the Organizer. New York: Oxford University Press. 1988</ref> to independent discoveries of both [[Hans Spemann]] of Germany in 1901<ref>Spemann, H. Über Korrelationen in der Entwicklung des Auges/On correlations in the development of the eye. Verh. anat. Ges. Jena 15, 61-79. 1901</ref> and Warren Lewis of the USA in 1904.<ref>Lewis, WH Experimental studies on the development of the eye in amphibia. I. On the origin of the lens in Rana palustris. Amer. J. Anat. 3, 505-536. 1904</ref> It was [[Hans Spemann]] who first popularized the term “primary neural induction” in reference to the first differentiation of ectoderm into neural tissue during neurulation.<ref name="Organizer">Spemann, H. & H. Mangold, Über Induktion von Embryonalanlagen durch Implantation artfremder Organisatoren/On induction of embryo anlagen by implantation of organizers of other species. Archiv mikroskop. Anat. Entwicklungsmech. 100, 599-638 1924</ref><ref>Spemann, H. & H. Mangold 1924: Induction of embryonic primordia by implantation of organizers from a different species. In: B.H. Willier & J.M. Oppenheimer (eds.), Foundations of Experimental Embryology, (translated 1964 ed.), Englewood Cliffs, New Jersey: Prentice-Hall, p. 144-184</ref> It was called "primary" because it was thought to be the first induction event in embryogenesis. The Nobel prize-winning experiment was done by his student [[Hilda Mangold]].<ref name= "Organizer"/> Ectoderm from the region of the dorsal lip of the blastopore of a developing salamander embryo was transplanted into another embryo and this "organizer" tissue “induced” the formation of a full secondary axis changing surrounding tissue in the original embryo from ectodermal to neural tissue. The tissue from the donor embryo was therefore referred to as the inducer because it induced the change.<ref name= "Organizer"/> While the organizer is the dorsal lip of the blastopore, this is not one set of cells, but rather is a constantly changing group of cells that migrate over the dorsal lip of the blastopore by forming apically constricted bottle cells. At any given time during [[gastrulation]] there will be different cells that make up the organizer.<ref>Gordon, R., N. K. Björklund & P. D. Nieuwkoop. Dialogue on embryonic induction and differentiation waves. Int. Rev. Cytol. 150, 373-420. 1994</ref>

Subsequent work on inducers by scientists over the 20th century demonstrated that not only could the dorsal lip of the blastopore act as an inducer but so could a huge number of other seemingly unrelated items. This began when boiled ectoderm was found to still be able to induce by [[Johannes Holtfreter]].<ref>Holtfreter, J. Eigenschaften und Verbreitung induzierender Stoffe/Characteristics and spreading of inducing substances. Naturwissenschaften 21, 766-770. 1933</ref> Items as diverse as low pH, cyclic AMP, even floor dust could act as inducers leading to considerable consternation.<ref>Twitty, VC, Of Scientists and Salamanders Freeman, San Francisco, CA.1966</ref> Even tissue which could not induce when living could induce when boiled.<ref>Spemann, H., F.G. Fischer & E. Wehmeier Fortgesetzte Versuche zur Analyse der Induktionsmittel in der Embryonalentwicklung/Continued attempts at analysis of the cause of induction means in embryonic development. Natuwissenschaften 21, 505-506. 1933</ref> Other items such as lard, wax, banana peels and coagulated frog’s blood did not induce.<ref>Weiss, P.A.. The so-called organizer and the problem of organization in amphibian development. Physiol. Rev. 15(4), 639-674. 1935</ref> The hunt for a chemically based inducer molecule was taken up by developmental molecular biologists and a vast literature of items shown to have inducer abilities continued to grow.<ref>De Robertis, E.M., M. Blum, C. Niehrs & H. Steinbeisser, goosecoid and the organizer. Development (Suppl.), 167-171. 1992</ref><ref>Hahn, M. & H. Jäckle Drosophila goosecoid participates in neural development but not in body axis formation. EMBO J. 15(12), 3077-3084. 1996</ref> More recently, the inducer molecule has been attributed to genes and in 1995, there was a call for all the genes involved in primary neural induction and all their interactions to be catalogued in an effort to determine “the molecular nature of Spemann’s organizer”.<ref>De Robertis, E.M. Dismantling the organizer. Nature 374(6521), 407-408. 1995</ref> Several other proteins and growth factors have also been invoked as inducers including soluble [[growth factors]] such as [[bone morphogenetic protein]], and a requirement for “inhibitory signals” such as [[Noggin (protein)|noggin]] and [[follistatin]].

Even before the term induction was popularized, several authors, beginning with Hans Driesch in 1894,<ref>Driesch, HAE. Analytische Theorie der Organischen Entwicklung/Analytic Theory of Organic Development. Leipzig: Verlag Von Wilhelm Engelman. 1984</ref> suggested that primary neural induction might be mechanical in nature. A mechanochemical-based model for primary neural induction was proposed in 1985 by G.W. Brodland and [[Richard Gordon (theoretical biologist)|R. Gordon]].<ref>Gordon, R. Brodland, GW. The cytoskeletal mechanics of brain morphogenesis: cell state splitters cause primary neural induction. Gell Biophys. 11: 177-238. (1987)</ref>  An actual physical wave of contraction has been shown to originate from the precise location of the Spemann organizer which then traverses the presumptive neural epithelium<ref>Brodland, GW” Gordon, R, Scott MJ, Bjorklund NK, Luchka KB, Martin, CC, Matuga, C., Globus, M., Vethamany-Globus S. and Shu, D.  Furrowing surface contraction wave coincident with primary neural induction in amphibian embryos. J Morphol. 219: 131-142. 1994</ref> and a full working model of how primary neural inductions was proposed in 2006.<ref>Gordon, NK, Gordon R [https://link.springer.com/article/10.1186/s12976-016-0037-2 The organelle of differentiation in embryos: the cell state splitter] Theor Biol Med Model (2016) 13: 11. https://doi.org/10.1186/s12976-016-0037-2</ref><ref>Björklund, NK, Gordon, R [http://www.ijdb.ehu.es/web/paper.php?doi=052102nb A hypothesis linking low folate intake to neural tube defects due to failure of post-translation methylations of the cytoskeleton] [[International Journal of Developmental Biology]] 50 (2-3), 135-141</ref> There has long been a general reluctance in the field to consider the possibility that primary neural induction might be initiated by mechanical effects.<ref>{{cite book | url=http://www.worldscientific.com/worldscibooks/10.1142/2755 | doi=10.1142/2755 | title=The Hierarchical Genome and Differentiation Waves | series=Series in Mathematical Biology and Medicine | year=1999 | volume=3 | publisher=World Scientific Publishing Company | isbn=978-981-02-2268-0 }}</ref> A full explanation for primary neural induction remains yet to be found.