Neurulation refers to the folding process in vertebrate embryos, which includes the

transformation of the neural plate into the neural tube.[1] 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.[2]
Different portions of the neural tube form by two different processes, called primary
and secondary neurulation, in different species.[citation needed]

• 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

•
• Cross section of a vertebrate embryo in the neurula stage

•
• A description of the neurulation process in three dimensions.
• Primary neural induction
• The concept of induction originated in work by Pandor in the 1817.[3] The
first experiments proving induction were attributed by Viktor Hamburger[4] to
independent discoveries of both Hans Spemann of Germany in 1901[5] and
Warren Lewis of the USA in 1904.[6] 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.[7][8] 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.[7] 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.[7] It is important to
note that while the organizer is the dorsal lip the blastopore, this is not one set
of cells but rather is a constantly changing group of cells that are migrating
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.[9]
• 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 induce by Johannes
Holtfreter.[10] Items as diverse as low pH, cyclic AMP, even floor dust could
act as inducers leading to considerable consternation.[11] Even tissue which
could not induce when living could induce when boiled.[12] Other items such
as lard, wax, banana peels and coagulated frog’s blood did not induce.[13] 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.[14][15] 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”.[16] 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,[17] suggested that primary neural induction might
be mechanical in nature. A mechanochemical based model for primary neural
induction was proposed in 1985 by Brodland &Gordon.[18] 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[19] and a full working model of how primary neural inductions was
 proposed in 2006.[20][21] There has long been a general reluctance in the field
to consider the possibility that primary neural induction might be initiated by
mechanical effects.[22] A full explanation for primary neural induction
remains to be found.
• Shape change[edit]
• 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.[23][24] 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.[25] See Neural plate
• Folding[edit]
• 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 causes 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. Neural plate folding is a
complicated step.[citation needed]
• 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 notochodral 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.[citation needed]
• 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.[26] 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.[27]
• Patterning

•
• Transverse section of the neural tube showing the floor plate and roof plate
• According to the French Flag model where stages of development are
directed by gene product gradients, several genes are considered important
for inducing patterns in the open neural plate, especially for the development
of neurogenic placodes. These placodes first become evident histologically in
the open neural plate. After sonic hedgehog (SHH) signalling from the
notochord induces its formation, the floor plate of the incipient neural tube
also secretes SHH. After closure, the neural tube forms a basal or floor
plate and a roof or alar plate in response to the combined effects of SHH and
factors including BMP4 secreted by the roof plate. The basal plate forms
most of the ventral portion of the nervous system, including the motor
portion of the spinal cord and brain stem; the alar plate forms the dorsal
portions, devoted mostly to sensory processing.[28]
• The dorsal epidermis expresses BMP4 and BMP7. The roof plate of the
neural tube responds to those signals by expressing more BMP4 and
other transforming growth factor beta (TGF-β) signals to form a
dorsal/ventral gradient among the neural tube. The notochord expresses SHH.
The floor plate responds to SHH by producing its own SHH and forming a
 gradient. These gradients allow for the differential expression of transcription
factors.[28]
• Complexities of the model
• Neural tube closure is not entirely understood. Closure of the neural tube
varies by species. In mammals closure occurs by meeting at multiple points
which then close up and down. In birds neural tube closure begins at one
point of the midbrain and moves anteriorly and posteriorly.[29][30]
• Secondary neurulation
• In secondary neurulation, the neural ectoderm and some cells from the
endoderm form the medullary cord. The medullary cord condenses, separates
and then forms cavities.[31] These cavities then merge to form a single tube.
Secondary neurulation occurs in the posterior section of most animals but it is
better expressed in birds. Tubes from both primary and secondary neurulation
eventually connect at around the sixth week of development.[32]
• Early brain development
• The anterior portion of the neural tube forms the three main parts of the
brain: the forebrain (prosencephalon), midbrain (mesencephalon), and
the hindbrain (rhombencephalon).[33] These structures initially appear just
after neural tube closure as bulges called brain vesicles in a pattern specified
by anterior-posterior patterning genes, including Hox genes,
other transcription factors such as Emx, Otx, and Pax genes, and secreted
signaling factors such as fibroblast growth factors (FGFs) and Wnts.[34] These
brain vesicles further divide into subregions. The prosencephalon gives rise
to the telencephalon and diencephalon, and the rhombencephalon generates
the metencephalon and myelencephalon. The hindbrain, which is the
evolutionarily most ancient part of the chordate brain, also divides into
different segments called rhombomeres. The rhombomeres generate many of
the most essential neural circuits needed for life, including those that control
respiration and heart rate, and produce most of the cranial nerves.[33] Neural
crest cells form ganglia above each rhombomere. The early neural tube is
primarily composed of the germinal neuroepithelium, later called
the ventricular zone, which contains primary neural stem cells called radial
glial cells and serves as the main source of neurons produced during brain
development through the process of neurogenesis.[35][36]
• Non-neural ectoderm tissue[edit]
• Paraxial mesoderm surrounding the notochord at the sides will develop into
the somites (future muscles, bones, and contributes to the formation of limbs
of the vertebrate ).[37]
• Neural crest cells
 Masses of tissue called the neural crest that are located at the very edges of
the lateral plates of the folding neural tube separate from the neural tube and
migrate to become a variety of different but important cells.[citation needed]
• Neural crest cells will migrate through the embryo and will give rise to
several cell populations, including pigment cells and the cells of the
peripheral nervous system.[citation needed]
• Neural tube defects
• Failure of neurulation, especially failure of closure of the neural tube are
among the most common and disabling birth defects in humans, occurring in
roughly 1 in every 500 live births.[38] Failure of the rostral end of the neural
tube to close results in anencephaly, or lack of brain development, and is
most often fatal.[39] Failure of the caudal end of the neural tube to close
causes a condition known as spina bifida, in which the spinal cord fails to
close.[40]