Question

1. There are two main types of cells in the human brain, neurons (nerve cells) and glial cells (supporting cells). Once neurons fully mature, these nerve cells no longer divide. Glial cells, however, continue to divide over a person’s entire lifetime.

1. GDNF (glial cell line-derived neurotrophic factor) is a small protein that stimulates growth in glial cells. What kind of signal molecule is this protein?

2. How does GDNF likely promote cell division? After the glial cell receives GDNF, what will happen in the next phase of the cell cycle?

3. Once a glial cell has received this signal and continues through the cell cycle, name and describe the other two checkpoints that a glial cell must encounter in order for it to fully divide.
   1. Checkpoint 2:

2. Checkpoint 3:

4. Is cancer more likely to develop in the neurons or the glial cells? Why?

5. Define proto-oncogenes and tumor suppressor genes.
   1. Proto-oncogene:

2. Tumor suppressor gene:

6. How can changes in these genes lead to cancer?
   1. Changes in proto-oncogenes?

2. Changes in tumor suppressor genes?

7. There are many different kinds of brain tumors, as classified by the World Health Organization (WHO). To attempt to understand all these different kinds of brain tumors, a group of scientists based in Germany have begun the Molecular Neuropathology project (MolecularNeuropathology.org) to track changes in DNA methylation patterns seen in tumor cells. What are two ways that changes in DNA methylation patterns can lead to cancer?
   1. Cancer causing changes in DNA methylation 1:

2. Cancer causing changes in DNA methylation 2:

Answer 1

Solution:

a) GDNF acts as growth factor signal molecule. They helps survive glial cells. The GDNF molecules generally binds to GFRalpha1 receptors. GDNFs were initially discovered as a potent survival factor for midbrain dopaminergic neurons in the CNS.

b)  GDNF activates the cortical microglial cells through binding to the receptors GFRα-1 and cRET and activating downstream signaling through the MAP Kinase pathway. MAP kinase pathway is one of the imopratant regulatory pathway that induces the expression of many genes. Many sugnaling intermediates in this pathway like  Ras, are proto-oncogens. The GDNF also acts through PI3 Kinase(PI3K) pathway.. By acting through this pathway the GDNF induces the survival of nerves and also cortical neuroprotection from necrotic cell death and also from programmed cell death. These growth factors might be activating the cell cycle stages by down regulatiing the cell cycle checkpoint protein retinoblastoma(Rb).

c) We can consider the intra-S-phase checkpoint as the second check point encountered. This is followed by a checkpoint p53 mediated checkpoint before the cell gets entered into mitosis. Because this checkpoint ensures that only undamaged DNAs enters mitosis. During mitosis several other regulations must be encountered by the cell to exit from the present cell cycle.

d) Cancers aree most likely to deveolop in glial cells. Because unlike neurons glial cells divide throughout the life time of an organism. The neuronal cells generally exits through a phase after mitotic exit called as G0 phase. Where as these glial cells again enters G1 phase for further division.

e) Proto-oncogenes are those genes whose upregulation induces cancer. A dominant gain of function mutation causes the upregulation of proto-oncogenes thus they convert into oncogenes and helps induce uncontrolled cell division that eventually leads to cancer. eg; Ras

Tumor suppresor genes on the other hand helps protect a cell from uncontrolled proliferetion by developing several cell-cycle checkpoints. The recessive loss of function mutation to tumor suppresor genes causes the downregulation of their functions and may thus leads to cancer. eg; Retinoblastoma, p53