Well, just to look at the big picture now of inductive signalling, and this is a slide from the book that gives you way more detail than I care for you to know in this course, but it does represent a paradigm that I want you to appreciate. And that paradigm is what we might call a transcriptional code. Which reflects the coordinated expression of inductive signals that are coordinated both in location, but also in developmental time. And this interaction of inductive signalling is what gives rise to regional identity within the developing nervous system. It helps to differentiate one location in the brain stem or spinal cord from another. It also establishes the dorsal ventral access of the developing neural tube, which is critical for the development of sensory neurons. As well as columns of cells that give rise to our motor output from the brain stem and the spinal cord. So, these inductive signals really provide for the establishment of the identity of distinct populations of neurons that are necessary for the expression of mature function in the human brain and spinal cord. Now, a similar transcriptional code is responsible for the formation of regions that go on to form our forebrain, our telencephalon and our .diencephalon. We know quite a bit less about how this works in the forebrain than in the hindbrain and the spinal cord, but we're beginning to understand some of the inductive signals that are responsible for forming the cerebral cortex, the basal ganglia, other deep forebrain structures, as well as the derivatives of the diencephalon, including the optic cup and the otic placode, which goes on to form the structures that are necessary for vestibular function and then, auditory function. Well, once regional identity has been established along the length of the developing neural tube, the next major challenge is proliferation. Making the cells that are necessary to properly populate the grey matter structures of the developing brain and spinal cord. And proliferation is just mind-boggling in the developing nervous system. We know that in the adult brain there are about 100 billion neurons and if that number doesn't stagger the mind, consider that there are at least that many, and probably several fold greater than that number, glial cells in the human central nervous system. So just an incredible number of cells are present in the brain and the spinal cord. And in order to produce so many cells, the rate of proliferation is just staggering. During the peak of the production of cells in the developing nervous system, scientists have estimated that perhaps as many as 250,000 cells are produced every minute in the developing embryo. Another amazing aspect of the proliferation of brain cells, in early development, is that the production of neurons is restricted in time to a very narrow period. Nearly all the neurons that we have in our central nervous system right now were born in the second trimester of pregnancy. Now there are some brain structures, like the cerebellum, that has just the enormous number of cells, and I'm referring to the granule cell population of the cerebellum. And it takes a considerable longer period of time to populate this cerebellum, so at least a year, perhaps as long as two years, but with the exception of the cerebellum, virtually all of the cells that we have in our brain and spinal cord were born in that second trimester of pregnancy. Now some of you may know that there is adult neurogenesis, that is, even right now there are new neurons being born, but, as we'll come to in a few tutorials, the genesis of those new neurons is restricted to the hippocampus, at least in our brain and it is perhaps very important that this phenomenon occurs, it may contribute to learning and memory and other aspects of maintaining our mental and physical health, but it is a restricted population of cells that grow into that one region of the brain. And, as far as we know now, the impact of the stem cells that may reside in the human brain, seems to be limited. Both in terms of, normal physiological function and the response of the brain to injury. So, I think there are fairly profound implications for this restriction of neurogenesis in the formation of the nervous system. The neurons that we have right now, are the ones that were born in that second trimester of pregnancy. So I would encourage you to think about that. And wonder, well, what are the implications for learning and memory? What are the implications for rehabilitation following injury, if that's, if that's the case. Maybe that's something that we can kick over to the discussion board. And, see if that might inspire some interesting dialogue. Well, let's talk a little bit about how this proliferation of brain cells occurs, and then we can go on to talk about how brain cells are differentiated into neuronal or glial fates. Brain cells, like most other cells in the body, go through the usual stages of growth. And the synthesis of new DNA, setting the stage for the division of the cell into daughter cells, and that division occurs via a process that we call mitosis. I certainly am assuming that you are broadly familiar with cell division from your prior studies of cell and molecular biology so I won't go into the details of how mitosis occurs. Rather I'd like to talk about how mitosis happens in the walls of the neural tube that allows for the production of the cells that come to populate specific gray matter structures that we recognize in the human brain such as the cerebral cortex or the basal ganglia. Well, proliferation occurs among a population of precursor cells in the walls of the neural tube. These precursor cells have a recognizable cell body containing the nucleus, and all the other organelles that are common to the cells of our body. And that cell body, then, grows a process that makes contact with the inner and the outer surface of this wall of the developing neural tube. The outer surface will, will become the piall surface surface of the brain, and the inner surface is, of course, the inner surface of the neural tube, that goes on to differentiate into the ependymal lining of the ventricles in the human brain. Now, along this path between the pial surface and the ventricle surface this cell body becomes multal. That is, it migrates in the up and down directions, towards the pia, and then back towards the lumen of the ventricle. So, as this cell body begins to translocate up towards the pial surface, the cell now enters the synthesis stage, where DNA is being replicated. And then, as DNA is replicated, the cell body then migrates back down towards the luminal surface of this developing neural tube as the cell gets ready for division. And it's near the ventricular surface then of this neural tube that mitosis occurs. And mitosis can happen in a symmetrical way. It can produce two precursor cells that can go through this, this dance of migrating to the pial surface and back to the luminal surface again, and undergo subsequent cycles of mitosis producing more daughter cells, or there can be what's called asymmetrical division. An asymmetrical division produces two different kinds of cells. One cell remains a progenitor cell, which can go on to subsequent stages of mitosis. Although it's mitotic potential now is somewhat limited. The other daughter cell becomes what we call a neuroblast and this is now a post-mitotic cell that can go on to differentiate into neurons or glial cells. Now once this neuroblast has been produced through this process of asymmetrical mitosis, for many of these cells, they migrate away from the ventricular region of the wall of the neural tube to a more peripheral destination. And that migration is important for forming a structure like the cerebral cortex. So now we're looking a little bit further along in development. And now the wall of the neural tube is beginning to become a bit more complex. And if we look at this wall of neural tube in some detail, we can recognize the ventricular zone, where mitosis is happening, but increasingly, we begin to develop a separation between the pial surface and the luminal surface and the wall of the neural tube. And we begin to populate a structure that now acquires the properties of gray matter. And this structure, we call the cortical plate. The cortical plate is the first formation of the cerebral cortex. So, the challenge here is to get these neuroblasts that are formed here in the ventricular surface up to the cortical plate. And this requires a process of migration. So, the cells must become motile, and they must find their way to this outward cortical plate. And the way this happens is these neuroblasts will migrate along a radial fiber that is formed by a presumptive glial cell, we call this the radial glial cell. So these are essentially precursor cells now that continue to maintain their contact between the pial surface and the luminal surface of the developing neural tube and this long extended process becomes a pathway for the migration of the neuroblast. So, over here to the right, we have a dipiction of one of these neuroblast migrating along this radial glial fiber and these cells will translocate, they will shimmy along this fiber on their way towards the cortical plate. So there are a variety of factors that guide this migration. And, along the way, these neuroblasts begin to further differentiate and acquire a specific identity that will allow them to be differentiated into a neuron or a glia or a particular sub type of one of those broad categories of brain cells. So, as these neuroblasts migrate from the ventricular zone up to the cortical plate, they do so in a particular pattern. the cortex is essentially built in an inside out fashion and here are some data from what's called birth dating studies that have been done to track the final mitosis of a precursor cell and its ultimate position within the developing cortical plate. Well, there's a technical means by which this can be done. It's described in a box in chapter 22, if you're interested in how this happens. But essentially, what we can do is, we can label precursor cells at a particular point in development, and simply ask what has become of the post mitotic neuroblasts that were derived from that population of precursor cells that were marked at a particular time of development. And what this approach has taught us is that the cortex does indeed develop in an inside out fashion. The cells that are born in, let's say, the late first trimester of pregnancy come to populate the inner and the outer margins of the cortical plate. And thereafter, as we progress through the second trimester of pregnancy, the cells that are born early in that second trimester come to reside in the lower portion of the cortical plate, in the region that ultimately differentiates into cortical layer six, the inner layer of the cortex that sits just on top of the white matter. And as neurogenesis progresses through that second trimester of pregnancy, extending at least in some cortical regions into the third trimester, we see this progressive population of the cortical plate from the inner layers to the outer layers such that the last cells to take up their residence in the developing cortical plate are those that reside in what would become cortical layers two and three. So these neurons that come to reside in the outer part of the cortex have to migrate through these cells that have already established residence in the deeper layers of the cortex. And as these cells migrate through these deeper layers of the cortex, there is yet additional opportunity for inductive signalling to influence the fate of these later born and more superficial residing cells in the developing cortex. So this is the pattern by which a cortex is constructed. An inside out pattern involving the precise regulation of neurogenesis and the migration of neuroblast. So, obviously there's a lot of specification that's going on here. Cells are born at a particular time. They are provided the signals that are essential for migration and for getting off that radial glial fiber at the appropriate location such that the cortex is progressively built out in this inside out pattern. Now unfortunately, we know that some of the signals that are responsible are subject to genetic mutation. Perhaps they can be influenced by environmental toxins or dietary factors. And there are some known phenotypes where this inside-out pattern is destructive. In fact, the process of neuronal migration and the proper establishment of this inside-out pattern seems to be essential for establishing the identity of the cells that take up residence in these various layers of the cortex. And their location, as you may recall, has much to do with determining the connections of the neurons that are ending up in one cortical layer or another. So if this process of migration and patterning of the cortex is disrupted, it's very likely that also the connections of those cells will likewise be disrupted. And we now know that there are a number of congenital malformations of the cerebral cortex that reflect errors in the migration of these neuroblasts. We think that perhaps even subtle errors in the migration of these neurons might be responsible for some forms of mental retardation and learning disability. Although there's much more work that needs to be done to truly understand what's going on at the level, at the level of cortical development that can be related to the broad spectrum of learning disabilities that we confront in society. We'll say more about that topic as the story of cortical maturation continues in subsequent tutorials.
