Neurulation refers to the folding process in
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
embryos, which includes the transformation of the
neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
into the
neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...
. The embryo at this stage is termed the
neurula
A neurula is a vertebrate embryo at the early stage of development in which neurulation occurs. The neurula stage is preceded by the gastrula stage; consequentially, neurulation is preceded by gastrulation. Neurulation marks the beginning of th ...
.
The process begins when the
notochord induces the formation of the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS) by signaling the ectoderm
germ layer above it to form the thick and flat
neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
. The neural plate folds in upon itself to form the
neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...
, which will later differentiate into the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
and the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, 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. The first experiments proving induction were attributed by
Viktor Hamburger
Viktor Hamburger (July 9, 1900 – June 12, 2001)Garland E. AllenViktor Hamburger, 1900–2001. National Academy of Sciences Biographical Memoirs, 2015, 39 pp. was a German-American professor and embryologist. His collaboration with neuroscie ...
to independent discoveries of both
Hans Spemann
Hans Spemann (; 27 June 1869 – 9 September 1941) was a German embryologist who was awarded a Nobel Prize in Physiology or Medicine in 1935 for his student Hilde Mangold's discovery of the effect now known as embryonic induction, an influence ...
of Germany in 1901 and Warren Lewis of the USA in 1904. It was
Hans Spemann
Hans Spemann (; 27 June 1869 – 9 September 1941) was a German embryologist who was awarded a Nobel Prize in Physiology or Medicine in 1935 for his student Hilde Mangold's discovery of the effect now known as embryonic induction, an influence ...
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 1924] 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
Hilde Mangold (20 October 1898 – 4 September 1924) (née Proescholdt) was a German embryologist who was best known for her 1923 dissertation which was the foundation for her mentor, Hans Spemann's, 1935 Nobel Prize in Physiology or Medicin ...
.
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.
It is important to note that 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 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.
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
Johannes Holtfreter (January 9, 1901 – November 13, 1992) was a German-American developmental biologist whose primary focus was the “organizer,” a part of the embryo essential for the development of the proper body plan.
Biography
Holtf ...
. Items as diverse as low pH, cyclic AMP, even floor dust could act as inducers leading to considerable consternation. Even tissue which could not induce when living could induce when boiled. Other items such as lard, wax, banana peels and coagulated frog’s blood did not induce. 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. 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”. Several other proteins and growth factors have also been invoked as inducers including soluble
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...
such as
bone morphogenetic protein, and a requirement for “inhibitory signals” such as
noggin
Noggin may refer to:
General
* Noggin or gill (volume), a unit of volume
* Noggin (cup), a small cup
* Noggin, slang for head
A head is the part of an organism which usually includes the ears, brain, forehead, cheeks, chin, eyes, nose, an ...
and
follistatin.
Even before the term induction was popularized several authors, beginning with Hans Driesch in 1894, 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. 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 and a full working model of how primary neural inductions was proposed in 2006. 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
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
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
Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
and
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
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 Apical constriction is the process in which contraction of the apical side of a cell causes the cell to take on a wedged shape. Generally, this shape change is coordinated across many cells of an epithelial layer, generating forces that can bend o ...
. 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. See
Neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
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
The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with primary neurulation, meaning that it forms by the coming together of t ...
and the creation of the
neural groove
The neural groove is a shallow median groove of the neural plate between the neural folds of an embryo. The neural plate is a thick sheet of ectoderm surrounded on either side by the neural folds, two longitudinal ridges in front of the primit ...
. The neural folds form
dorsolateral hinge points
Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position pro ...
(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. Neural plate folding is a complicated step.
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.
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
The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide ...
at
Carnegie stage 9 (around Embryonic day 20 in
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...
s). 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
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...
embryos, the
cranial neuropore closes approximately on day 24 and the caudal neuropore on day 28. Failure of the cranial (superior) and caudal (inferior) neuropore closure results in conditions called
anencephaly
Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube ...
and
spina bifida
Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, men ...
, respectively. Additionally, failure of the neural tube to close throughout the length of the body results in a condition called
rachischisis.
Patterning
![Gray640](https://upload.wikimedia.org/wikipedia/commons/2/20/Gray640.png)
According to the
French Flag model
The French flag model is a conceptual definition of a morphogen, described by Lewis Wolpert in the 1960s. A morphogen is defined as a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular ...
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
The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis f ...
and a roof or
alar plate
Daminozide—also known as aminozide, Alar, Kylar, SADH, B-995, B-nine, and DMASA,—is a plant growth regulator, a chemical sprayed on fruit to regulate growth, make harvest easier, and keep apples from falling off the trees before they ripen s ...
in response to the combined effects of SHH and factors including
BMP4
Bone morphogenetic protein 4 is a protein that in humans is encoded by ''BMP4'' gene. BMP4 is found on chromosome 14q22-q23.
BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfamil ...
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.
The dorsal epidermis expresses BMP4 and
BMP7
Bone morphogenetic protein 7 or BMP7 (also known as osteogenic protein-1 or OP-1) is a protein that in humans is encoded by the ''BMP7'' gene.
Function
The protein encoded by this gene is a member of the TGF-β superfamily. Like other members o ...
. The roof plate of the neural tube responds to those signals by expressing more BMP4 and other
transforming growth factor beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
(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.
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.
Secondary neurulation
Primary neurulation develops into secondary neurulation when the caudal neuropore undergoes final closure. The cavity of the spinal cord extends into the neural cord. 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. 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.
In humans, the mechanisms of secondary neurulation plays an important role given its impact on the proper formation of the human posterior spinal cord. Errors at any point in the process can yield problems. For example, retained medullary cord occurs due to a partial or complete arrest of secondary neurulation that creates a non-functional portion on the vestigial end.
Early brain development
The anterior portion of the
neural tube
In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...
forms the three main parts of the brain: the
forebrain
In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...
(
prosencephalon
In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...
),
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
(
mesencephalon
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...
), and the
hindbrain
The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephal ...
(
rhombencephalon
The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephal ...
).
These structures initially appear just after neural tube closure as bulges called
brain vesicle
Brain vesicles are the bulge-like features of the early development of the neural tube in vertebrates. Vesicle formation begins shortly after anterior neural tube closure at about embryonic day 9.0 in the mouse and the fourth and fifth gestational ...
s in a pattern specified by anterior-posterior patterning genes, including
Hox genes
Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the co ...
, other
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s such as Emx, Otx, and Pax genes, and secreted signaling factors such as
fibroblast growth factor
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...
s (FGFs) and
Wnts
WNTS (1590 AM) is a commercial radio station licensed to Beech Grove, Indiana, and serving the Indianapolis metropolitan area. It broadcasts a Classic Regional Mexican radio format and is owned by Marvin Kosofosky's Continental Broadcast Group ...
. These brain vesicles further divide into subregions. The prosencephalon gives rise to the
telencephalon
The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb. In ...
and
diencephalon, and the
rhombencephalon
The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephal ...
generates the
metencephalon
The metencephalon is the embryonic part of the hindbrain that differentiates into the pons and the cerebellum. It contains a portion of the fourth ventricle and the trigeminal nerve (CN V), abducens nerve (CN VI), facial nerve (CN VII), and a port ...
and
myelencephalon
The myelencephalon or afterbrain is the most posterior region of the embryonic hindbrain, from which the medulla oblongata develops.
Development
Neural tube to myelencephalon
During fetal development, divisions of the neural tube that give ...
. The hindbrain, which is the evolutionarily most ancient part of the
chordate
A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These fi ...
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.
Neural crest cell
Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, ...
s form
ganglia above each rhombomere. The early neural tube is primarily composed of the
germinal neuroepithelium Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or ...
, later called the
ventricular zone
In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, whi ...
, which contains primary
neural stem cell
Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...
s called
radial glial cell
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ...
s and serves as the main source of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s produced during brain development through the process of
neurogenesis.
Non-neural ectoderm tissue
Paraxial mesoderm
Paraxial mesoderm, also known as presomitic or somitic mesoderm is the area of mesoderm in the neurulating embryo that flanks and forms simultaneously with the neural tube. The cells of this region give rise to somites, blocks of tissue running ...
surrounding the notochord at the sides will develop into the
somites
The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide i ...
(future muscles, bones, and contributes to the formation of limbs of the
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
).
Neural crest cells
Masses of tissue called the
neural crest
Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...
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.
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.
Neural tube defects
Failure of neurulation, especially failure of closure of the neural tube are among the most common and disabling
birth defect
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...
s in humans, occurring in roughly 1 in every 500 live births. Failure of the rostral end of the neural tube to close results in
anencephaly
Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube ...
, or lack of brain development, and is most often fatal. Failure of the caudal end of the neural tube to close causes a condition known as
spina bifida
Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, men ...
, in which the spinal cord fails to close.
See also
*
Embryonic differentiation waves
A mechanochemical based model for primary neural induction was first proposed in 1985 by Brodland and Gordon. They proposed that there is a mechanically sensitive bistable organelle made of microtubules and microfilaments in the apical end ...
*
Neural fold
The neural fold is a structure that arises during neurulation in the embryonic development of both birds and mammals among other organisms. This structure is associated with Neurulation#Primary neurulation, primary neurulation, meaning that it ...
*
Neural plate
The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ant ...
*
Neural crest
Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...
References
Further reading
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External links
Overview at uvm.eduNeurulation Animation
{{Development of nervous system
Embryology of nervous system