Okay, so I introduced two categories of molecules that help mediate the signalling that's required to grow circuitry in the developing nervous system. We talked about Cell-associated molecules, now let's talk about the Diffusible molecules. And there are essentially molecules that are secreted by target tissues and diffuse out into the extracellular fluids. These molecules can affect the growth and the survival of neurons and their processes whether they be dendritic branches or axons. There are two categories of diffusible molecules, based on their mechanisms of action and how they affect the development of the neuron and its processes. I'd like to talk first about tropic molecules. These are molecules that guide the growth of axons toward or away from the source of this particular molecule. So, the directed growth is what we mean when we talk about tropism and so this is a tropic molecule that directs the growth of an axon. They comes essentially in two functional valences, they can be chemo attracted molecules. Or, chemo-repellent molecules. So, I'd like to give you some examples of each. There are also trophic molecules. So, while tropism refers to directed growth, trophism refers to nourishment. So, these are molecules that provide some kind of nourishment. Now, not nourishment in the form of glucose to be burnt up or ATP to be hydrolyzed and release energy from the chemical bonds. But nourishment in a way that promotes the survival and the growth of neurons and their processes. In the peripheral nervous system these trophic molecules become relly important. In matching the axonal innervation with the target tissue that's present. And, we'll also see the importance of trophic molecules for development of appropriate circuits within the central nervous system as well. Now one, very important and very interesting aspect Of trophic molecule production is that this is activity dependent. So this will provide the basis for competitive interactions in developing circuits. So very interesting concept, we'll say more about that in our next tutorial. So let's consider some examples of our diffusible molecules. So again the general mode. Of operation here is that these are molecules that are secreted by target tissues. And these molecules interact with receptors that are present on the surface of growth cone. These diffusible molecules interacting with their receptors can have widespread effects on the neuron. that transduces these signals. There can be local effects that can affect the growth patterns at the level of the growth cone and the individual axonal branch in question. But there might also be signals that go back to the cell body and affect gene transcription in the entire cell. So there are a variety of consequences of the interaction of these diffusable molecules with their receptors. So, in this figure, we see an illustration of several, different kinds of diffusable molecules, and their effect. we see some source of, diffusable chemo attractant signals here. That begin to divert the growth of an axon towards that source of that chemoattractant. We also see contact-mediated chemoattractant signals that are important for helping to establish the growth of axons in parallel. and this is critical for the formation of axonal pathways, where there are many hundreds of thousands of axons, typically, growing together in parallel. Now, there are also chemorepellant signals that can be produced at some local source. And you'll see that as a growth cone begins to approach and explore, it may interact with one of these signals and then be diverted away to grow in the opposite direction from that source. There may also be a contact mediated chemo repulsion signals That help to make sure that the growth cones at the leading edge of a developing pathway, begin to explore, the entire environment. Giving these growth cones an opportunity to seek out appropriate sources of chemo attractant. And avoid the appropriate. Sources of chemo repellents. Now also in this figure, we see the presence of trophic molecules that are expressed and they don't necessarily direct the growth of an axon into the source of that trophic support. Rather what they do is they validate that growth. So the growth is directed by the Tropic molecules but the survival and the ability of that axon and the neuron that gave rise to that axon to thrive, is dependant in some measure on the acquisition of tropic support. That comes through the inteaction of these neuro [UNKNOWN] molecules and their reeceptors. We'll say more about that in just a moment. First I'd like to gove you some examples of some of the tropic molecules and then talk about one very important pathway, that illustrates the operation of these milecules in development. So, there are several representatives of these Trophic molecules that we now know about. On the left, we see examples of the Netrin and Slit Family of trophic molecules. Netrin. Is a soluble protein that is released and interacts with its receptors DCC and an associated protein called Unc5. So these interactions can result in the assembly of Actin filaments, leading to the directed growth. Of that growth cone, and its axon being elongated in it wake towards the source of netrin. Now, there's a related, tropic molecule called slit that interacts with the receptor called robo. And slit antagonizes the activity of netrin. So. Netrin and slit together provide sort of a push, pull system, or a go, stop kind of system that allows for the direction of growth. And this is particularly important at those forks in the road, as I'll show you in just a moment. Now another defusable trophic molecule illustrated here. Are the semaphorins. So semaphorins are cell associated molecules that can be released and diffuse away from their source. And the semaphorins can interact with receptors. two of them illustrated here, plexin and neuropilin. These receptors can likewise interact with transduction machinery that can affect the assembly of [UNKNOWN] skeleton and the patterened growth of that growth column. However, what the Semaphorins end to do is, promote the disassembly. Of these neuronpillaments and that results in the retraction or the collapse of the phalapaudia and the lamelapaudia/g. So the semaphorins are important signals that mediate the repulsive signals that are encountered as axons explore their environment. So, let's consider one pathway. And indeed this is the pathway that I had in mind in our study question a little while ago. this pathway is the spinothalamic tract. Now recall the second order axon of the spinothalamic pathway. It has to do something which I find completely remarkable. This axon is grown out by a neuron in the dorsal horn of the spinal cord. And this happens throughout the entire length of the spinal cord. The axon will grow out very near its level of origin. And it will begin to grow in the anterior medial direction. So that axon encounters the mid line of the spinal cord and the ventral while commissure, the interior white commissure of the spinal cord. And it makes an important growth choice. It grows across that mid line and enters the anterolateral white matter on the contralateral side of the spinal cord. So, there is a decision to cross a mid-line here in the outgrowth of this second order axon. But there's also one more remarkable aspect to the growth pattern. Once across the mid-line and into the anterolateral part of the white matter, this axon now makes a hard turn in the superior direction. And grows to the ventral posterior complex of the thalamus. So the implication is that there must be some chemo attracted signal that draws this axon towards the anterior midline of the spinal cord. And then once across the midline, there must be some signal that directs the growth. away from that segment of origin, and towards the superior axis. So we imagine there may be some combination of chemoattractant, and chemorepellant molecules that achieve the necessary pattern of growth for this second order axon to establish the spinothalamic tract. And indeed, what we imagine happening with the growth of this pathway Is these second order axons, these commissural axons are attracted towards the region of the floorplate. And they're attracted by the presence of netrin, which is secreted by this special region of the neurepithelium called the floorplate. So these axons begin to grow in towards that floorplate. And then once grow across that floorplate, now slit seems to be produced just lateral to the location of that floorplate. And slit now begins to negate the influence of netrin. And there is likely some other kind of signal, some other repulsive signal, that is present here in the anterolateral part of the developing neural tube. Perhaps a semaphorin, which will collapse the growth cone from growing in this direction, and rather promote growth away from the source of that chemorepellant. there very likely is also some kind of chemo-attractant that is in some concentration gradient drawing this axon towards the superior aspect of the developing hindbrain, even into the forebrain, reaching its ultimate target in the diencephalon. So this is a wonderful example of how the presence of chemo retractant and chemo repellent molecules can mediate what are really some spectacular patterns of growth that we've learned about in our survey of the structure of the sensory motor systems. I'll refer you to a beautiful box in chapter 23, that talks about another famous fork in the road. That would be the optic chiasm. Where similar functions, seem to direct the nasal retinal axons across the optic chiasm, while repelling the temporal retinal axons which remain on the ipsilateral side of the brain, progressing through the ipsilateral optic tract. So, turn to the box there in chapter 23 to learn more about that particular pathway.
