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 lumenal surface. They are joined at the lumen of the tube by junctional complexes, where they form a pseudostratified layer of epithelium called neuroepithelium. Neuroepithelial cells are the stem cells of the central nervous system, known as neural stem cells, and generate the intermediate progenitor cells known as radial glial cells, that differentiate into neurons and glia in the process of neurogenesis.
Embryonic neural development
Brain development
During the third week of embryonic growth, the brain begins to develop in the early fetus in a process called morphogenesis. Neuroepithelial cells of the ectoderm begin multiplying rapidly and fold in forming the neural plate, which invaginates during the fourth week of embryonic growth and forms the neural tube. The formation of the neural tube polarizes the neuroepithelial cells by orienting the apical side of the cell to face inward, which later becomes the ventricular zone, and the basal side is oriented outward, which contacts the pia, or outer surface of the developing brain. As part of this polarity, neuroepithelial cells express prominin-1 in the apical plasma membrane as well as tight junctions to maintain the cell polarity. Integrin alpha 6 anchors the neuroepithelial cells to the basal lamina. The neural tube begins as a single layer of pseudostratified epithelial cells, but rapid proliferation of neuroepithelial cells creates additional layers and eventually three distinct regions of growth. As these additional layers form the apical-basal polarity must be downregulated. Further proliferation of the cells in these regions gives rise to three distinct areas of the brain: the forebrain, midbrain, and hindbrain. The neural tube also gives rise to the spinal cord.
Neuroepithelial cell proliferation
Neuroepithelial cells are a class of stem cell and have the ability to self-renew. During the formation of the neural tube, neuroepithelial cells undergo symmetric proliferative divisions that give rise to two new neuroepithelial cells. At a later stage of brain development, neuroepithelial cells begin to self renew and give rise to non-stem cell progenitors, such as radial glial cells simultaneously by undergoing asymmetric division. Expression of Tis21, an antiproliferative gene, causes the neuroepithelial cell to make the switch from proliferative division to neuronic division. Many of the neuroepithelial cells also divide into radial glial cells, a similar, but more fate restricted cell. Being a more fate restricted cell the radial glial cell will either generate postmitotic neurons, intermediate progenitor cells, or astrocytes in gliogenesis. During neuroepithelial cell division, interkinetic nuclear migration allows the cells to divide unrestricted while maintaining a dense packing. During G1 the cell nucleus migrates to the basal side of the cell and remains there for S phase and migrates to the apical side for G2 phase. This migration requires the help of microtubules and actin filaments.
Radial glial cell transition Neuroepithelial cells give rise to radial glial progenitor cells in early embryonic development. To make this change, neuroepithelial cells begin to downregulate their epithelial features, by stopping the expression of occludin, a tight junction protein. Loss of occludin causes a loss of the previous tight junction seals which is required for the generation of neuroblasts. Another tight junction protein, PARD3, remains at the apical side of the cell co-localizing with N-cadherin and keeps the apical face of the neuroepithelial cell intact. In the absence of occludin some polarity is still lost and the neuroepithelial cell gives rise to the radial glial cell.
Adult neurogenesis
Genesis of neuroepithelial cells in the adult CNS In the adult CNS, neuroepithelial cells arise in several different areas of the brain: the subventricular zone (SVZ), the olfactory bulb and the dentate gyrus of the hippocampus. These cells do not appear in any of the peripheral nervous system. Often categorized as neural stem cells, neuroepithelial cells give rise to only a few varieties of neural cells, making them multipotent - a definite distinction from the pluripotent stem cells found in embryonic development. Neuroepithelial cells undergo mitosis generating more neuroepithelial cells, radial glial cells or progenitor cells, the latter two differentiating into either neurons or glial cells. The neuroepithelial cells undergo two different forms of mitosis: asymmetric differentiating division and symmetric prolific division. The asymmetric cell division results in two different varieties of daughter cells (i.e. a neuroepithelial cell divides into a radial glial cell and another neuroepithelial cell), while the symmetric version yields identical daughter cells. This effect is caused by the orientation of the mitotic spindle, which is located in either the posterior or anterior area of the mitotic cell, rather than the center where it is found during symmetric division. The progenitor cells and radial glial cells respond to extracellular trophic factors - like ciliary neurotrophic factor (CNTF), cytokines or neuregulin 1 (NRG1) - that can determine whether the cells will differentiate into either neurons or glia. On a whole, neurogenesis is regulated both by many varied regulatory pathways in the CNS as well as several other factors, from genes to external stimuli such as the individual behavior of a person. The large interconnected web of regulatory responses acts to fine-tune the responses provided by newly formed neurons.
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