Your friend’s dog, Spot, jumped onto a table with a terrarium housing your pet s

Question

Your friend’s dog, Spot, jumped onto a table with a terrarium housing your pet salamander, Lizzie. Unfortunately, the table tipped over and Spot has suffered a head injury which damaged the primary motor cortex. Lizzie lost most of the distal right forelimb in the accident. Please answer the following questions regarding the nervous system and regeneration,

A. Starting at the epiblast, describe five developmental events leading up to the generation of upper motor neurons that reside in layer 5 of the motor cortex.

B. You employ a published IPSC approach to generate cortical layer 5 neurons in a culture dish from Spot’s fibroblasts. After transplanting them into the brain lesion site, the neurons must regenerate axons and synapse. Describe two cytoskeletal components crucial for axonal outgrowth and how extracellular cues modulate this process. Propose an experimental manipulation that would promote synapse formation?

C. Compare epimorphosis and morphallaxis. Describe an example of each.

D. Lizzie just so happened to be part of the experiment by the Tanaka group in which they transplanted GFP fluorescently labeled cartilage into its limbs (see Nov. 9 lecture). Describe where GFP positive cells are found in Lizzie’s forelimb after it regenerates. Provide an explanation for these observations.

Explanation / Answer

A)

Upper motor neurons are created in the motor cortex region of the brain and brain stem. These motor neurons are developed from the fibroblasts. The fibroblasts are reprogrammed into pluripotent stem cells which undergo neural induction to form neural progenitors. Sometimes, fibroblasts also can be reprogrammed into neural progenitors. The pluripotent stem cells and neural progenitors undergo transcriptional programming and patterning respectively to give rise to motor neurons.

The developmental stages that exist from the transformation of the stem cells to the spinal cord consisting of motor neurons are blastocyst, ectoderm, neuroectoderm, neural tube, embryonic central nervous system later divided into forebrain, midbrain, hindbrain and spinal cord.

B)

Regeneration of axons readily happens in the peripheral nervous system than in the central nervous system. After the injury of the peripheral nerves, axons immediately regenerate. The distal region of the axon that is away from the cell body will undergo Wallerian degeneration leading to the disintegration and fragmentation of axon. The waste is cleaned by the glial cells and macrophages. The proximal portion of the axons will regenerate and attach to the target cells to start the axon function.

There are certain regeneration associated genes that are up regulated by the neurons of the peripheral nervous system. Some of these genes have direct role in the regeneration of axons. Active genes include c-Jun, activating transcription factor -3, SRY box containing gene 11, small proline-repeat protein 1A, growth associated protein -43 and CAP-23.

The growth inhibitory interactions supported by the membrane associated components regulate the attachment of axons to the targets and help in the formation of the synapse. The extracellular semaphorins, netrins, ephrins, repulsive guidance molecules and slits interact with the axonal receptors, plexins, neuropilins to generate the axonal guidance for the synapse formation necessary for the functioning of the nervous system.

C)

Regeneration is classified into two types based on its mode of activity. When the newt limb is regenerated, some part of the limb remains with the formation of blastema at the wounded site. This blastema eventually regenerates the lost tissues and further into the organs. This is called epimorphic regeneration which can be referred to as “add-on” regeneration. Here, the old cells provide the origin for the regeneration of the lost tissue. In the other type of regeneration, no blastema is formed at the wound site and regeneration occurs with the drastic rearrangement of the remaining tissues. This type of regeneration modeling is called as morphallaxis. Regeneration is classified based on whether the blastema is formed or not near the wound site. An example for epimorphosis can be newt and that of morphallaxis is Hydra.

D)

The entire regenerated tissue from the fluorescent labeled cartilage will possess the GFP positive cells present in the regenerated forelimb of the salamander lizzie. This is because, the regenerated tissue has originated from the transplanted cartilage.

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