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Thread: Cell adhesion molecules

  1. #1

    Cell adhesion molecules

    Dr. Young,

    There appears to be a good deal of interest in the role of cell adhesion molecules in research, particularly with L1 and Laminin. Would you mind giving a brief overview of the functional role of CAMs in regeneration?

    Also, you mentioned in an earlier post that axons love to grow on Laminin expressing substrates, but they are reluctant to leave and venture into areas that do not express Laminin. When growing axons on such substrates, will they grow the length of substrate and then stop or will they just find a nice "sunny" spot on the substrate and stop? If the former, would it be possible to test axon growth on a Laminin expressing substrate with small non-Laminin expressing gaps? (Similar to the brief gaps in myelination at synapse junctions.)

    Thanks.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  2. #2
    Quote Originally Posted by Steven Edwards
    Dr. Young,

    There appears to be a good deal of interest in the role of cell adhesion molecules in research, particularly with L1 and Laminin. Would you mind giving a brief overview of the functional role of CAMs in regeneration?

    Also, you mentioned in an earlier post that axons love to grow on Laminin expressing substrates, but they are reluctant to leave and venture into areas that do not express Laminin. When growing axons on such substrates, will they grow the length of substrate and then stop or will they just find a nice "sunny" spot on the substrate and stop? If the former, would it be possible to test axon growth on a Laminin expressing substrate with small non-Laminin expressing gaps? (Similar to the brief gaps in myelination at synapse junctions.)

    Thanks.
    Both laminin and L1 are so-called cell adhesion molecules although L1 belongs to a very special class of cell adhesion molecules called the immunoglobulin superfamily. Let me first talk about L1 since it is simpler and perhaps better understood.

    L1 is a neural cell adhesion molecule that is expressed on the surface of growing neurons and axons. It is both a cell adhesion molecule as well as a receptor. It is a long molecule that has an cytoplasmic domain, five fibronectin type II repeats, and then 6 immunoglobulin domains. L1 binds to other L1 molecules, as well as other cell adhesion molecules such as laminin. Because L1 is expressed by growing axons and L1 bind to L1, it is responsible for axons growing together in bundles, a process called fasciculation. If you block L1, axons start to grow separately from each other. The reason why your spinal tracts and peripheral nerves grow in bundles is in part due to L1. Absence or mutations of L1 cause significant deficits of neural development.

    This is a picture from http://zygote.swarthmore.edu/cell9.html

    We (see Huang, et al. 2003) had earlier discovered that a soluble form of L1 (an L1 dimer created by using human Fc to hold the two L1 molecules in a Y-shape molecule) will stimulate regeneration and recovery of function in animals. Recently, my colleage Marty Grumet found that the combination of L1 and stem cell transplants work better than either one alone. Normally, L1 is not expressed in high levels in uninjured spinal cords. In injured spinal cords, while growing axons express L1, glial cells do not express much L1.

    Laminin is a "universal" cell adhesion molecule. It is a basement membrane extracellular molecule that serves as the basis for migration of many different kinds of cells, including epithelial cells, fibroblasts, neurons and leukocytes. The function and structure of Laminin (often called laminin-5) is well conserved across evolution. For example, human cells bind to rat laminin and rat cells bind to human laminin. The receptors for laminin are called integrins, particularly integrins a3b1 and a6b4. Neurons express integrin a3b1 and this receptor is known to modulate neuronal migration during brain and spinal cord development. Expression of integrin in adult neurons will promote neurite outgrowth.

    The L1 cell adhesion molecule also binds to laminin and activation of L1 receptors on neurons will spur axonal growth. The interesting thing is that neurotrophins will upregulate L1 expression on neurons. Melitta Schachner first discovered and named L1 in mouse. However, a similar molecule present in rat and called NILE (for NGF-induced large extracellular) protein turns out to be L1 in rat. Thus, neurotrophins will increase expression of L1 receptors that will not only respond to L1 but also to laminin and other cell growth promoting adhesion molecules in the spinal cord. L1 also bind to Nr-CAM, a cellular adhesion molecules discovered by Marty Grumet and is now attracting a great deal of excitement because it appears to be the primary cell adhesion molecule that is responsible for signalling where axons turn when decussating and where myelin is formed on axons, and other crucial guidance roles.

    Does this help?

    Wise.
    Last edited by Wise Young; 07-31-2005 at 12:19 PM.

  3. #3
    It definitely helps answer the first question. Thanks.

    I hadn't considered that a CAM could bind to itself, although there's no reason to believe it couldn't.

    Thanks again.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  4. #4
    Steven, I don't know the answer to your second questions but can point out some interesting phenomena that may shed light on how axons interact with cell adhesion molecules.

    Cell adhesion molecules are not unlike tire treads. They must stick to the road but not stick so tightly that the tires will not roll. In order to grow, the growth cones of axons must adhere to molecules in the extracellular space and then detach from them in order to move. So, the process is one of sequential attachment and detachment.

    The process of attachment and detachment are not well understood. Several possible mechanisms may play a role. First, when a cellular adhesion molecule attaches to a receptor, the receptor will inactivate and it will transiently detach. By the way, this is a typical behavior of many receptors and their ligands. Second, the growth cone (the growing tip of the axon) has an array of receptors. Part of the growth cone may be exploring forward while another part is attached. When the exploring tip attaches, it may tell the prior attached part to detach. Third, there may be a mixture of attractive and repelling molecules in the extracellular space and also mixture of receptors on the axon that balances the attraction and repelling effects of the environment.

    The concept that there is a mixture of attractive and repelling extracellular molecules is becoming well accepted. For example, various forms of another class of celllular adhesion molecules called semaphorins will attract or repel a growing axon. It is possible that the two known repellant molecules, Nogo and chondroitin-6-sulfate proteoglycan (CSPG), are mixed in with attractive molecules such as L1 and laminin-like molecules in the extracellular space. We should also remember that axons not only grow on extracellular matrix molecules but also cell surfaces.

    There is another curious phenomenon that scientists have been studying. People have been asking the question of how axons grow across patterns of laminin and CSPG. Jerry Silver showed in the early 1990's that neurons will initially send axons that grow on strips of CSPG. However, the moment that the axons touch laminin, they will refuse to go back onto CSPG again. Likewise, if grow neurons on a surface of CSPG and put a drop of laminin onto the surface of the culture dish. When a growing axon contacts the laminin, it will start growing around and around inside the drop of laminin and a little neuroma.

    Several years ago, Jerry showed a remarkable movie of how axons grow in an increasing or decreasing gradient of laminin and CSPG. What he did was to dry a drop of CSPG solution placed on a laminin coated surface. When the drop dries, it forms a circular field of CSPG against a background of laminin, with increasing CSPG concentration towards the outer border of the drop. He then placed neurons into the middle of the CSPG field overlaid on a laminin background. The neurons start sending axons outward but, as the CSPG concentration increases, the growth cone of the axon begin to get very big and bulbous and eventually look like one of the terminal end bulbs that we often see in injured spinal cords. Ramon y Cajal described these terminal end bulb over 100 years ago and suggested that they are the "sterile" endbulbs of injured axons that have stopped growing. Jerry Silver took time lapse movies of axons growing in an increasing gradient of CSPG against a background of laminin, showing that the axons continuously try to grow ahead and then falls back, backward and forward. He calls them "frustrated growth cones".

    Other scientists have investigated what happens if they polkadotted the tissue culture dish with laminin, to ask the question that if there were another laminin dot that is close by, will the axon grow to the next and and so on. It turns out that they will. Another interesting possibility is that when axons grow in bundles, they don't really pay all that much attention to the environment. The axons on the inside of the bundle will see each other and only a few "pioneer" axons may be necessary to get a bundle of axons to regenerate in the peripheral nerve or spinal cord.

    Our goal in L1 treatment is to administer soluble L1 to overcome the inhibitory effects of Nogo and CSPG, and other inhibitory proteoglycans including neurocan and phosphocan. The solube L1 should stimulate L1 receptors on the growing axons and hopefully allow them to get through areas of where there may be significant inhibition. The L1 was given intrathecally and allowed to percolate into the spinal cord. It is possible that the KDI peptide is acting the same way as soluble L1 in that it is binding on to axonal receptors and encouraging the axons to grow despite the presence of growth inhibitory molecules.

    Wise.
    Last edited by Wise Young; 07-31-2005 at 03:34 PM.

  5. #5
    Wise, thanks for the informative reply.

    The laminin polkadotting sounds similar to what I was thinking of. Based on the bundling nature of axons and Silver showing that axons continually try to move forward, it would be interesting to test your idea of pioneering axons. It would also be interesting to see if the volume of the axon bundle effects the ability of axons to migrate through non-permissive environments (e.g., can a larger bundle migrate through a longer stretch of non-permissiveness than a smaller one) and, if so, does passing through the non-permissive environment prune the axon bundle?

    Thanks again. I really appreciate posts like this where we can find out what the limits of our knowledge are.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

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