User:KMaher123/Neural Fold

The Neural Fold is the structure, or fold, formed during the neurulation stage of development which forms the neural tube. While the neural fold is not a specific cell type, there are many defined types of cells and structures which are involved with the neural fold and folding. Important molecules and proteins are responsible for the neural fold and there are documented disorders associated with problems with the formation of the neural tube categorized as neural tube defects.

Introduction
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 involution of tissue layers, rather than a clustering, and subsequent hollowing out, of individual cells (which is called secondary neurulation). In humans, the neural folds are responsible for the formation of the anterior end of the neural tube. The neural folds are derived from the neural plate, a preliminary structure consisting of elongated ectoderm cells. The folds give rise to neural crest cells, as well bringing about the formation of the neural tube.

Origin
In the embryo, the formation of the neural folds originates from an area called the Neural Ectoderm-Epidermal Ectoderm, or NE-EE. This region of the embryo is formed after gastrulation and is where the epithelial tissue of the embryo folds the neural crest and plate inward to form the neural tube and the neural crest cells, as shown in the thumbnail below.

Folding Mechanism


The formation of the neural fold is initiated by the release of calcium. The released calcium interacts with proteins that can modify the actin filaments in the outer epithelial tissue, or ectoderm, in order to induce the dynamic cell movements necessary to create the fold. These cells are held together by cadherin (specifically E-cadherin), a type of intercellular binding protein. Since all of the cells of the neural plate are expressing this same type of cadherin, they are able to adhere to each other; similarly, when the cells at the peaks of the neural folds come in proximity with each other, it is this affinity for similar cadherin molecules that allows these cells to bind to each other. Thus, when the neural tube precursor cells begin expressing N-cadherin in the place of E-cadherin, the cells no longer associate, causing the neural tube to separate from the ectoderm and settle inside the embryo. When the cells fail to associate in a manner that is not part of the normal course of development, severe diseases can occur.

Process Overview
The process of folding begins when the cells in the central region of the neural plate, the medial hinge point cells, bind to the notochord beneath them. This creates a central anchoring point for the process of folding to occur, and subsequently creates the neural groove. As the neural folds continue to extend, dorsolateral hinge points (DLHP) form, allowing them to conform into a tube-like structure. When the peaks of the folds (the neural crest region) touch, they merge and involute, creating the neural tube beneath the newly formed epidermal layer.

Mechanism
The molecular mechanism behind this process lies in the modulation of bone morphogenic proteins. Bone morphogenic proteins (BMPs) are a wide family of proteins that perform many functions throughout the growing embryo, including stimulating the growth of cartilage and bone. In order to allow for the growth of precursor neural tissues, as opposed to precursor bone or cartilage tissues, BMP expression is decreased in the neural plate, specifically along the medial line, where the neural groove will soon form. The proteins produced from the genes Noggin and Chordin inhibit these BMPs, and subsequently allow neural commitment genes, like Sox, to be expressed. These genes encode transcription factors, which alter the genomic expression of these cells, furthering them along the path of neural cell commitment. This process of BMP inhibition allows for the anchoring of the medial hinge point cells, providing the neural folds with the foundation necessary for folding and closure to occur. Noggin and Chordin have other roles in the neurulation process, including stimulating the neural crest cells to emigrate from the newly formed neural tube. The Sonic hedgehog gene also plays a role in attenuating BMP expression, forming the medial hinge point while inhibiting the formation of the dorsolateral hinge points, and in ensuring the proper closure of the neural folds. The prechordal plate, notochord, and non-neural ectoderm are believed to be important inducer tissues which release these chemical signals, in order to trigger neural plate folding.

The final adhesion of the converging neural folds is due to several different types of intercellular binding proteins. Cadherins and their CAM receptor molecules, for example, are present in two types in the neural precursor tissue: E-cadherin keeps the cells of the neural plate and surrounding ectoderm adhered to each other, while N-cadherin does the same for the cells of the neural fold. Only cells expressing the same kind of cadherin can bind to each other; since the peaks of the neural folds both express N-cadherin, they are able to merge into a continuous sheet of cells. Likewise, it is this diminished affinity between cells expressing different types of cadherin that allows the neural tube precursor cells to separate from the ectoderm, forming the neural tube on the interior of the embryo and the true epidermis on the exterior. Another set of molecules involved with the merging of the neural folds are the ephrin molecules and their Eph receptors, which adhere in a similar manner to the cadherin molecules discussed above.

Derivative Structures
The merging of the neural folds gives rise to the neural tube, the precursor to the central nervous system, to neural crest cells, which give rise to a variety of diversemesenchymal cells, and to the true epidermal layer. The neural fold is an extremely important structure in that this mechanism is needed in order to produce these diverse kinds of cells in the right places.

Diseases
There are many potential diseases that can arise from the improper adhesion or merging of the neural folds. If the posterior neuropore fails to close, a condition called spina bifida can occur, in which the bottom of the spinal cord remains exposed. Often this condition can be detected during prenatal examinations and be treated before birth, though in more severe cases the individual may cope with the condition for the rest of his or her life. Depending on the severity and the affected area, individuals can experience a variety of symptoms, including a varying motor function and mobility, bladder control, and/or sexual function.

If the failure is instead in the anterior neuropore, anencephaly occurs. In this fatal condition, the brain tissue is directly exposed to the amniotic fluid, and is subsequently degraded. If the entire neural tube fails to close, the condition is referred to as craniorachischisis.

Introduction
We - Kelsey Maher, Daniel Fernandez, and Ryan Dikdan – are students of Dr. Laura Hake, and are enrolled in her Spring BI432 course Developmental Biology at Boston College. As part of our semester-long project, will be expanding the stub article of the neural fold.

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 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.

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 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 25 and the caudal neuropore on day 27 (Carnegie stages 11 and 13 respectively). Failure of the cranial (anterior) and caudal (posterior) neuropore closure results in conditions called anecephaly and spina bifida, respectively. Additionally, failure of the neural tube to close throughout the length of the body results in a condition called craniorachischisis.

Background Information on the Neural Fold
The neural fold is a structure that arises from the neural plate. Past research suggests that as the sides of the neural plate rise, the midline cells form the floor plate; the peripheral regions will become the dorsal portions of the tube. Current research seems to point to Hensen’s node as the point of origin for the neural tube located in the trunk of the organism, which becomes inserted into the neural plate during development. This was investigated by creating chimeric chickens with Hensen’s nodes comprised of quail cells. These quail cells gave rise to the caudal floor plate and the notochord, suggesting that Hensen’s node is the precursor to these structures. Recent studies suggest that the expansion of the extracellular matrix is responsible for driving the elevation of the neural fold, while other studies implicate that factors from the cranial mesenchyme may also have a significant effect.

Proposed Subtopics
-->
 * General Information
 * 1) Origins of the neural fold
 * 2) Tissues derived from the neural fold
 * 3) Characteristics of the neural fold
 * 4) Folding mechanism
 * Current Research
 * Clinical Significance
 * 1) Diseases/Conditions arising from mutations of the neural fold
 * Further Implications
 * See Also
 * References