| Neural fold | |
|---|---|
 Chick embryo of thirty-three hours’ incubation, viewed from the dorsal aspect. 30x. (Neural fold labeled at center left, third from the bottom.) | |
| Details | |
| Carnegie stage | 9 |
| Precursor | Neural plate |
| Gives rise to | Neural tube |
| Identifiers | |
| Latin | plica neuralis |
| TE | fold_by_E5.13.1.0.1.0.2 E5.13.1.0.1.0.2 |
| Anatomical terminology | |
Theneural fold is a structure that arises duringneurulation in the embryonic development of bothbirds andmammals among other organisms.[1][2] This structure is associated withprimary neurulation, meaning that it forms by the coming together of tissue layers, rather than a clustering, and subsequent hollowing out, of individual cells (known assecondary neurulation). In humans, the neural folds are responsible for the formation of theanterior end of theneural tube. The neural folds are derived from theneural plate, a preliminary structure consisting of elongatedectoderm cells. The folds give rise toneural crest cells, as well as bringing about the formation of theneural tube.[1][3]
In the embryo, the formation of the neural folds originates from the area where theneural plate and the surroundingectoderm converge. This region of the embryo is formed aftergastrulation, and consists of epithelial tissue. Here, the epithelial cells elongate by means ofmicrotubule polymerization, increasing their height. The thumbnail below shows this process, as well as the subsequent formation of the neural crest cells and the neural tube, which arise from the joining of the neural folds.[4]
The formation of the neural fold is initiated by the release ofcalcium from within the cells. The released calcium interacts with proteins that can modify theactin filaments in the outer epithelial tissue, or ectoderm, in order to induce the dynamic cell movements necessary to create the fold.[6] These cells are held together bycadherins (specifically E and N-cadherin), types of intercellular binding protein. When the cells at the peaks of the neural folds come in proximity with each other, it is the affinity for similarcadherin molecules (N-cadherins) 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, this causes the neural tube to form and separate from the ectoderm and settle inside the embryo.[1] When the cells fail to associate in a manner that is not part of the normal course of development, severediseases can occur.
The process of folding begins when the cells in the central region of the neural plate, the medial hinge point cells, bind to thenotochord beneath them. This creates a central anchoring point for the process of folding to occur, and subsequently creates theneural groove. As the neural folds continue to extend, dorsolateral hinge points form, allowing the folds to curve into a tube-like structure. When the peaks of the folds (known as the neural crest regions) touch, they merge and involute, creating the neural tube beneath the newly formed epidermal layer.[7]
The molecular mechanism behind this process lies in the expression and repression ofbone morphogenetic proteins (BMPs). 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 thegenesNoggin andChordin inhibit these BMPs, and subsequently allow neural commitment genes, likeSOX, to be expressed. These genes encodetranscription factors, which alter the genomic expression of these cells, furthering them along the path of neural cell commitment.[8]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 andChordin have other roles in the neurulation process, including stimulating the neural crest cells to emigrate from the newly formed neural tube.[9][10] TheSonic 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.[11]The prechordal plate, notochord, and non-neural ectoderm are believed to be important inducer tissues that release these chemical signals, in order to trigger neural plate folding.[8]
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.[1]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.[8]
The merging of the neural folds gives rise to many structures including the neural tube (the precursor to thecentral nervous system),neural crest cells(which give rise to a variety of diversemesenchymal cells), and to the trueepidermal layer.[1] The neural fold is an extremely important structure in that this mechanism is needed to produce these diverse kinds of cells in the right places.
There are many potential diseases that can arise from the improper adhesion or merging of the neural folds. During folding, the openings that are formed at thecranial andcaudal regions are termed the cranial and caudal neuropores.[12] If the caudal neuropore fails to close, a condition calledspina bifida can occur, in which the bottom of the spinal cord remains exposed. Often this condition can be detected duringprenatal 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.[13] 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.[14]
If the failure is instead in the cranial neuropore,anencephaly occurs. In this condition, the brain tissue is directly exposed to theamniotic fluid, and is subsequently degraded.[15] If the entire neural tube fails to close, the condition is referred to ascraniorachischisis.
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