Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube.Larsen WJ. Human Embryology. Third ed. 2001.P 86. The embryo at this stage is termed the neurula.
The process begins when the notochord induces the formation of the central nervous system (CNS) by signaling the ectoderm germ layer above it to form the thick and flat neural plate. The neural plate folds in upon itself to form the neural tube, which will later differentiate into the spinal cord and the brain, eventually forming the central nervous system. Computer simulations found that cell wedging and differential proliferation are sufficient for mammalian neurulation.
Different portions of the neural tube form by two different processes, called primary and secondary neurulation, in different species. In primary neurulation, the neural plate creases inward until the edges come in contact and fuse. In secondary neurulation, the tube forms by hollowing out of the interior of a solid precursor.
Primary neurulation
Primary neural induction The concept of induction originated in work by Pandor in 1817.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 The first experiments proving induction were attributed by Viktor HamburgerHamburger, V.. The Heritage of Experimental Embryology: Hans Spemann and the Organizer. New York: Oxford University Press. 1988 to independent discoveries of both Hans Spemann of Germany in 1901Spemann, H. Über Korrelationen in der Entwicklung des Auges/On correlations in the development of the eye. Verh. anat. Ges. Jena 15, 61-79. 1901 and Warren Lewis of the USA in 1904.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 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.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 1924Spemann, 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 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. 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. 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.Gordon, R., N. K. Björklund & P. D. Nieuwkoop. Dialogue on embryonic induction and differentiation waves. Int. Rev. Cytol. 150, 373-420. 1994
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.Holtfreter, J. Eigenschaften und Verbreitung induzierender Stoffe/Characteristics and spreading of inducing substances. Naturwissenschaften 21, 766-770. 1933 Items as diverse as low pH, cyclic AMP, even floor dust could act as inducers leading to considerable consternation.Twitty, VC, Of Scientists and Salamanders Freeman, San Francisco, CA.1966 Even tissue which could not induce when living could induce when boiled.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 Other items such as lard, wax, banana peels and coagulated frog's blood did not induce.Weiss, P.A.. The so-called organizer and the problem of organization in amphibian development. Physiol. Rev. 15(4), 639-674. 1935 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.De Robertis, E.M., M. Blum, C. Niehrs & H. Steinbeisser, goosecoid and the organizer. Development (Suppl.), 167-171. 1992Hahn, M. & H. Jäckle Drosophila goosecoid participates in neural development but not in body axis formation. EMBO J. 15(12), 3077-3084. 1996
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".De Robertis, E.M. Dismantling the organizer. Nature 374(6521), 407-408. 1995 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 and follistatin.
Even before the term induction was popularized, several authors, beginning with Hans Driesch in 1894,Driesch, HAE. Analytische Theorie der Organischen Entwicklung/Analytic Theory of Organic Development. Leipzig: Verlag Von Wilhelm Engelman. 1984 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 R. Gordon.Gordon, R. Brodland, GW. The cytoskeletal mechanics of brain morphogenesis: cell state splitters cause primary neural induction. Gell Biophys. 11: 177-238. (1987) 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 epitheliumBrodland, 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 and a full working model of how primary neural inductions was proposed in 2006.Gordon, NK, Gordon R The organelle of differentiation in embryos: the cell state splitter Theor Biol Med Model (2016) 13: 11. https://doi.org/10.1186/s12976-016-0037-2Björklund, NK, Gordon, R 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 There has long been a general reluctance in the field to consider the possibility that primary neural induction might be initiated by mechanical effects. A full explanation for primary neural induction remains yet to be found.
Shape change As neurulation proceeds after induction, the cells of the neural plate become high-columnar and can be identified through microscopy as different from the surrounding presumptive epithelial ectoderm (epiblastic endoderm in amniotes). The cells move laterally and away from the central axis and change into a truncated pyramid shape. This pyramid shape is achieved through tubulin and actin in the apical portion of the cell which constricts as they move. The variation in cell shapes is partially determined by the location of the nucleus within the cell, causing bulging in areas of the cells forcing the height and shape of the cell to change. This process is known as apical constriction.Burnside. M. B. Microrubules and microfilaments in amphibian neurulation. Alii. Zool. 13, 989-1006 1973Jacobson, A.G. & R. Gordon. Changes in the shape of the developing vertebrate nervous system analyzed experimentally, mathematically and by computer simulation. J. Exp. Zool. 197, 191-246. 1973 The result is a flattening of the differentiating neural plate which is particularly obvious in salamanders when the previously round gastrula becomes a rounded ball with a flat top.Bordzilovskaya, N.P., T.A. Dettlaff, S.T. Duhon & G.M. Malacinski (1989). Developmental-stage series of axolotl embryos [Erratum: Staging Table 19-1 is for 20°C, not 29°C]. In: J.B. Armstrong & G.M. Malacinski (eds.), Developmental Biology of the Axolotl, New York: Oxford University Press, p. 201-219. See Neural plate.
Folding The process of the flat neural plate folding into the cylindrical neural tube is termed primary neurulation. As a result of the cellular shape changes, the neural plate forms the medial hinge point (MHP). The expanding epidermis puts pressure on the MHP and causes the neural plate to fold resulting in neural folds and the creation of the neural groove. The neural folds form dorsolateral hinge points (DLHP) and pressure on this hinge cause the neural folds to meet and fuse at the midline. The fusion requires the regulation of cell adhesion molecules. The neural plate switches from E-cadherin expression to N-cadherin and N-CAM expression to recognize each other as the same tissue and close the tube. This change in expression stops the binding of the neural tube to the epidermis.
The notochord plays an integral role in the development of the neural tube. Prior to neurulation, during the migration of epiblastic endoderm cells towards the hypoblastic endoderm, the notochordal process opens into an arch termed the notochordal plate and attaches overlying neuroepithelium of the neural plate. The notochordal plate then serves as an anchor for the neural plate and pushes the two edges of the plate upwards while keeping the middle section anchored. Some of the notochordal cells become incorporated into the center section neural plate to later form the floor plate of the neural tube. The notochord plate separates and forms the solid notochord.
The folding of the neural tube to form an actual tube does not occur all at once. Instead, it begins approximately at the level of the fourth somite at Carnegie stage 9 (around embryonic day 20 in humans). The lateral edges of the neural plate touch in the midline and join together. This continues both cranially (toward the head) and caudally (toward the tail). The openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. In human embryos, the cranial neuropore closes approximately on day 24 and the caudal neuropore on day 28.Youman's Neurological Surgery, H Richard Winn, 6th ed. Volume 1, p 81, 2011 Elsevier Saunders, Philadelphia, PA Failure of the cranial (superior) and caudal (inferior) neuropore closure results in conditions called anencephaly and spina bifida, respectively. Additionally, failure of the neural tube to close throughout the length of the body results in a condition called rachischisis.
Patterning