Congenital Minamata Disease

                     Normal Development

             
             When methyl mercury or any other toxins have not tainted our bodies, we can expect normal development of our nervous system.  The Central Nervous system (CNS) has many integral functions that are crucial for everyday life.  It is organized in a way that there are many subdivisions and substructures, that all play a key role in normal functioning and key behavioral processes.   The CNS comprises of the brain (forebrain, midbrain, and hindbrain) and the spinal cord.  Due to the complexity of the structures in the nervous system and immense significance of processes controlled by the brain, the brain is designed in a way that each structure and subsection has a specific role.  Furthermore, we will focus on the process of cell migration and radial glial cells, normal functioning of the cerebellum, as well as the development of the cerebral cortex and its interaction with microglial cells, structures that are highly affected by methylmercury exposure.   (Gilbert 2010.)

Cell migration and radial glial cell differentiation in the Cerebrum
      In normal development of the brain, cells must mitotically divide and migrate to other locations.  In the developing brain, the cells lining the ventricles of the brain first proliferate and differentiate into neurons or glia. Afterwards, the cells migrate to form the layers of the cerebral cortex.  After primary neurulation, the original ectoderm is divided into three sets of cells: the neural tube, the neural crest, and the epidermis.  The neural tube gives rise to the brain, which further differentiates into several layers (Gilbert 2010). 
          The neural tube is composed of a layer of stem cells referred to as the germinal neuroepithelium. After about 5 weeks of gestation, the neural tube gives rise to three zones: the ventricular zone (VZ), the intermediate zone (mantle), and the marginal zone (MZ).  The mantle and the MZ form from cells that have divided from the VZ.  Soon after, the VZ divides to create the subventricular zone (SVZ) and these two zones form the neuroblasts. Neuroblasts from the mantle migrate on glial processes  to establish a second zone at the outer surface of the brain called the neocortex.  The neocortex becomes stratified into six layers of the cerebrum.  Each layer of the neocortex differs functionally from the other layers, resulting in a very specialized tissue. When the ventricular zone generates neuroblasts, these cells migrate outward along radial glial processes thereby establishing an “inside-out” development of the brain. This means the cells “born” first become the second most inner layer of the neocortex, and those “born” last are on the outside of the neocortex (Gilbert 2010).
       A radial glial cell is a neural precursor cell that divides and generates another VZ cell and a cell committed to a certain function. Surprisingly, the cell with the “old” centriole remains in the VZ to divide further. In mitosis, cells are divided by centrioles migrating to opposite poles and forming microtubules that separate sister chromatids and furthering cell division.  Microtubules play an enormous role in this process, because without them cells would not divide and result in a poorly formed cerebral cortex.  Also, microtubules are in the cytoskeleton of migrating neuroblasts and if not present, cells would not be able to migrate on glial cells. Furthermore, neurons need structural support in the axon and this is provided by microtubules. The adult forms of these cortex layers are not fully developed until childhood, thus indicating that any sort of poisoning that disrupts microtubule function will have a tremendous effect in the normal development of the brain (Gilbert 2010).

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Cell Migration, Differentiation of neural stem cells (NSC), and development of neurons and glial cells from the three zones(Sherman 2008.)
 Microglia and astrocytes
        
          Glia cells are major support cells of the nervous system.  There are many different types of glia cells: Astrocytes, microglia, oligodendrocytes, schwann cells, and radial glia.  We will focus on microglia and astrocytes, since they are affected in Congenital Minamata disease.  As stated earlier, radial glia cells are a neural precursor, which means they differentiate into neurons.  After they form, they differentiate into smaller astrocytes.
Astrocytes are star-shaped cells that wrap around the pre-synaptic terminals of a group of axons.  The astrocytes then pick up chemicals released by the axons and then release them back, assisting in coordination of activity of axons (Gilbert 2010).  
       Microglia are small cells that remove waste material such as viruses, fungi, and other microorganisms.  These are important since they serve as a protective measure against any foreign material entering the brain, in our case, methyl mercury.  We have a blood brain barrier that helps to keep out most chemicals out of the brain, but the microglia cells serve a major role in defense similar to the cells in the immune system(Eto et al. 1997).


Normal Development completed by Ashiya Hamarani and Arpana Neelmegh