Well the story of the developing nervous system really begins with this process that we call gastrulation. So gastrulation refers to an invagination of the developing embryo at a stage that we call the blastula. And this process of invagination in the blastula produces three principle germ layers. And those germ layers are the ectoderm, the most outer layer, the mesoderm, or the mesoderm, which is the middle layer, and then the endoderm, which is the inner of these three layers. This is a fundamental event in the developing embryo, and it sets the stage for the formation of the nervous system. Now one very important structure that is formed in this stage of development is something called the notochord. Now, the notochord is a long, rod-like structure that is derived from mesoderm. And, here if we make a cross section through this developing embryo, will see the notochord here in this central location cutting cross section. So, what's special about the notochord? Well, I'll say more about that as we progress and talk about inductive signalling. But the notochord is responsible for sending out chemical signals that interact with this ectoderm that overlies this rod-like structure that runs along the length of the embryo. And these chemical signals induce a change and the fate of the ectoderm that overlies this notochord. That region of this ectoderm differentiates into a colon epithelium that we call a neural plate. And this neural plate, or sometimes we call it neuroectoterm will begin the process of forming the entire central nervous system. So the notochord is responsible for reducing the differentiation from the neural plate. I should also mention that the notochord helps to establish our primary axis of orientation in the developing embryo. The notochord forms in a more dorsal position in the developing embryo. Now we'll call it a gastrula. And so the presence of the notochord helps us to find what is dorsal versus what is ventral. the length of the notochord establishes the anterior to posterior axis of the developing embryo. And the fact that it's a mid-line structure helps to define the axis from medial out to lateral, obviously, in both directions. So, the presence of the notochord helps to define the bilateral axis of symmetry in the developing nervous system. Well following gastrulation and the development of the notochord and the onset of inductive signaling that forms the neural plate, the next major phase of embryo genesis is called neurulation. Neurulation is defined by the initial formation of the nervous system. And what happens in neurulation is that the neural plate begins to rise up in it's lateral margins. And begins to close off in a process that will form a tube out of that neural plate. So this begins with the formation of a groove that runs the anterior to posterior length of the embryo just above the notochord. And as the walls of this neural tube begin to grow out, they begin to come together along the dorsal midline. And we can see that process transpiring over, weeks, three into week four in, human embryo genesis. Here we proceed a little bit further, and we can see that now the neural tube has actually closed off underneath this over lying ectoderm. And there is a progressive closure of this neural tube that begins near center of this developing neural tube and then extends out into the interior and posterior directions. So this process continues and now we're into, well into the fourth week of embryonic life. And we have the anterior end and the posterior end of this developing neural tube progressively closing. The anterior end of this developing neural tube is going to form the brain and the rest of its length, all the way down to the posterior tip is going to form the spinal cord. Now, I'd like to return to this concept of inductive signaling, and say a little bit more about it. Because it's at this stage in embryo genesis, neurulation, that the inductive signals derived from the notochord are so important. For defining many of the important regions of that developing neural tube that will set the stage for further differentiation into the brain and to the spinal cord. So if we back up just a little bit in neurulation, so over here to the left we have the folds of the neural plate beginning to come together to form the neural tube. And the notochord is giving rise to these chemical signals that are inducing these morphogenic events in this overlying neural plate. But in addition to simply inducing the folding of that neural, well I should not say simply, it's really an amazing feat in development. That such a thing would happen, but in addition to inducing the formation of this tube, the notochord is also giving rise to signals. That are specifying some particular regions and one particular region is that portion of the neural plate that directly overlays the notochord. This becomes a region that we call the floor plate. And this becomes quite important, because it in turn gives rise to inductive signals that will influence the surrounding portion of this neural tube. Now there's another special region, that responds to inductive signals, and that is found on the dorsal side of this developing neural tube. We call that the roof plate, and the roof plate will give rise to signals that will influence the dorsal aspect of this epithelium that is forming the walls of the neural tube. And one additional region I want to highlight for you is that in the ridge of this folding neural tube that begins to come together, there's a special population of cells here. That we call the neural crest. And the neural crest will actually pinch off from the margins of this neural plate as the neural tube is forming. And the neural crest ends up sitting just along the dorsal and lateral margins of the neural tube once that tube has formed. Now the neural crest is a source of many different types of cells that are derived from it. cells begin to differentiate and they begin to migrate away from this region of the neural crest. And as they migrate away, they are subject to chemical signals from the nearby structures in the mesenchyme and in the mesodermal derivatives, such as these somites that we see here, sitting just lateral to the neural tube. So, as these cells migrate away from that dorsal lateral neural crest. they are exposed to all kinds of signals that generate a rich variety of progeny of these neural crests. And these progeny include both neurons as well as non-neural structures. so, here's just a, a brief example of some of the derivatives of this neural crest. So the neural crest pro-generative cell can be influenced by various factors to form our sensory nerves that we find in structures like the dorsal root ganglia. Other signals can induce formation of the peripheral cells of the visceral motor system. And so that would include our ganglionic neurons that are are intervening our visceral tissues. so, essentially the entire peripheral nervous system, including the enteric nervous system, is derived from neural crust. And, as I mentioned, also non-neural structures who derive from neural crests, such as the chromaffin cells and the melanocytes and others that are not depicted here. Now, how is all this accomplished, how is this possible? Well, it is possible because of inductive signalling. If I can just back up to this slide again and just highlight the means by which these signaling interactions occur. So, I mentioned the notochord is a very important source of inductive signaling. the floorplate and the roofplate become important sources of inductive signaling. As do the somites and these mesenchyme cells, through which the neural crest derivatives must migrate. So, just to be clear, I've highlighted for you in the handout what I mean by inductive signalings, so let me just draw your attention to that. So, inductive signalling is the ability of a cell or tissue to influence the fate of nearby cells during development by the synthesis in secretion of chemical signals. Now these chemical signals are either steroid hormones or peptide hormones, so they have an impact on the transcription of genes in the cells. That they interact with. The precise timing of the expression of these inductive signals becomes crucial for the proper formation of the develping brain. So what we will see is that in order to form the nervous system correctly. These inductive signals need to be turned on and turned off in a very precise pattern in both space within the embryo. But also in terms of developmental time. And all of this is regulated in complex way that we're just now beginning to understand. And again, it's subject to probation that can produce various forms of defects in the developing brain, as inductive signals might be either blocked.