Well, now that you've been able to refresh your understanding of the anatomy of the adult form of the human brain in relation to the changes that took place in the neural tube, that gave rise to this fantastic form, what I would like to do is to begin to talk about some of the genetic and molecular mechanisms that are responsible for establishing regional identity along that developing neural tube that ultimately leads to the formation of the human brain. Well this story, really took off as biologists began to explore the genetic basis of development in invertebrate systems and of course one of our favorite invertebrate model systems in biology is the fruit fly, drosophila, and what was discovered is that there are a set of genes that help to define. The segments of the developing drosophila larva. So here is a representation of the drosophila larva. And what we appreciate of course, is that this animal has a segmented body plan. So what was discovered several decades ago is that the segmentation of this developing larva reflects the expression of particular genes that establish regional identity. Such as this first thoracic segment of the larvae, which goes on to form what we call the prothorax and the drosophila. and it's from that prothorax that particular. body parts emerge, such as this first limb that emerges from the transformed larva into the adult form. Well, much molecular and genetic biology has gone on over the decades, and we've come to recognize that this segmentation of the developing larvae into an adult form reflects the expression of what we call, in drosophila, Hox genes, and their homologues in mammalians, including humans are called homeotic genes. So, in the human genome, we now know that there are four clusters. Of these Hox genes or these homeotic genes. Sometimes we call them Homeobox genes. And these clusters are responsible, we think, for beginning to establish some regional identity in the developing nervous system. There is an anterior to posterior pattern of expression of these clusters. Of Homeotic genes that help to establish, for example, the various segments of the human spinal chord. And the major divisions of the brain stem. Well, why should this be important? Why should you be motivated to learn something about these homeotic genes? Well, I've already challenged you to consider in some detail, the anatomy of the differential regions of the human brain stem for one very good reason, to understand the location of the cranial nerves in relation to divisions of the brain. So, hopefully you recognize the, relation of the trigeminal nerve to the pons and at the junction of the pons and the medulla we have an abducens nerve which is not present in this particular specimen, but we see very nicely here our cranial nerve seven. The facial nerve. And certainly a very beautiful vestibulocochlear nerve present, cranial nerve eight. And even just, you can see I think here, just a few nerve roots of cranial nerve 12, between the medullary pyramids and the olive, which is present out here laterally. Well, the relationship of these cranial nerves to particular regions of the developing brain stem seems to reflect the specific expression of homeotic genes that help to identify regional identity along the length of the developing neural tube. This is especially important. For the specification of position within the developing brain stem. we see the expression of particular motor nuclei of the brain stem, for example, that seem to be derived from particular regions of the brain stem that express a set of these homeotic genes. So this is an example of genetic specification determining regional identity and there are probably inductive signals at work here that establish this identity. And one of the many outcomes of this kind of inductive signaling is the specification of the identity of neurons. That go on to form critical structures that are important for form and function in the human nervous system, including these cranial nerves. So, if you've wondered why are the nerves found exactly where they are in the human brain, part of the answer is going to have to do with the differential expression. Of homeotic genes at particular points in development and at particular locations along the length of the developing neural tube, especially in that region that goes on to form the brain stem. Well, next I'd like to turn our attention to. This matter of inductive signalling and give you a few examples, not to overwhelm you with molecular detail but rather to give you a feel for how inductive signalling works and how these signals that are secreted out into the extra-cellular spaces in the developing embryo. Can have such a formative impact on the fate of cells that are in the process of developing within the walls of the neural tube. Well, as I mentioned, inductive signaling really begins in earnest in nur relation as the neural tube begins to form. And signals are expressed by this notochord that begin to influence the differentiation of these special regions in the neural tube that establish a dorsal ventral access. There is a floor plate that begins to give rise to it's own signals. That will establish a ventral identity in this region of the developing neural tube. And I think you know enough now about the spinal cord to connect the dots here and realize that ventral identity is going to give rise to motor circuits and alpha motor neurons that will grow out and. Connect the central nervous system to effector systems, namely our stride and muscles. Meanwhile, this roof plate will give rise to inductive signals that establish a dorsal identity in the developing walls of the neural tube. And dorsal, I think is you reflect on your understanding of the spinal cord, implies the development of somatic sensory neurons that are receiving incoming information about the experiences of our peripheral tissues. And integrating them within the central nervous system, giving rise to. Local circuit connections, as well as long distant pathways that convey somatic sensory signals to more rostral regions of the developing brain. So, dorsal and ventral become really key regions within the developing neural tube that have an influence on the ultimate fate of the cells that are developing in those regions. So, I'd like to give you some specific examples of these inductive signals so you have a big of a feel for really what's going on here. So one of the best understood inductive signals is called retinoic acid. So retinoic acid is a small lipophilic molecule, metabolized from Vitamin A. It's a very important inductive signal and it's one of the principle substances that explains the importance of Vitamin A for early brain development. So, Retinoic Acid is synthesized and released as a [UNKNOWN] molecule. It can readily translocate through cellular membranes. And it can bind to a receptor within the cell, and that receptor becomes a transcription factor that translocates to the nucleus, and it can interact with other binding proteins and turn on particular genes. And so that's what we see here. We see retinoic acid interacting with its receptors and other complexes that can modulate gene expression. Now retinoic acid provides one of those examples where the life experience can have an impact on the developing brain. Insufficient Vitamin A in the diet of the mother can have an impact on the capacity to produce this important inductive signal and there can be deleterious consequences for the formation of the early nervous system. There is an additional problem that can be encountered with respect to retinoic acid signaling. And that is an excess of vitamin A. And there are a variety of dietary supplements and even topical agents that can be purchased for other reasons that include Vitamin A or Retinoic Acid, and excess Retinoic Acid in the developing embryo likewise can be extremely harmful. In fact Retinoic Acid can become what's called a teratogen which is a exogenous substance that can induce malformations in the developing embryo. If you'd like to learn a little bit more about this particular topic, I would refer you to box 22c found in our textbook, which gets you a little bit more of the back story regarding how Retinoic Acid signaling shapes the developing brain. Well, let's consider some other kinds of inductive signals. Most of our conductive signals are actually not, steroid hormones. They are peptide hormones. So, these are substances that are secreted and interact with surface bound receptors. And one of our peptide hormones that I'd like to talk just a little bit about is called bone morphogenetic protein or bmp for short. And the way bmp works is that it interacts with a surface receptor here we see, bmp being secreted. by one kind of cell and it interacts with this receptor. And the receptor is what we call a serine kinase. So this means that it phosphorylates a serine residue in target proteins. And this serine kinase phosphorylates a transcriptional regulator. Called s, m, a, d, or smad for short. This is an acronym you don't need to worry about, its name, but I do want you to understand something about how this system works. So, he activated smad then associates with additional helper proteins and this then trans-locates to the nucleus where it acts as a transcription regulator. Now, B M P signalling is especially important in mesodermal tissue. As the name implies Bone Morphogenetic Protein, bmp signaling can induce the development of bone cells. Now, in ectoderm, bmp signalling can induce the formation of epidermis or skin, unless bmp signal is controlled. And this is where these additional factors that are illustrated here come in. There are factors called noggin and chordin; they have somewhat fanciful names. That can antagonize the interaction of bmp with it's receptor. When noggin and chordin antagonize the bmp signaling pathway preventing BMP from interacting with it's surface bound receptor, that's ectoderm will be diverted from an epidermal fate. to a neural fade, with noggin and chordin, this tissue will differentiate into what we call the neuroectoderm, or the neural plate. Now, I think that this is a really cool and fascinating thought which I've highlighted for you in your tutorial notes, and that is That what these molecules noggin and chordin really do is they rescue this ectoderm from becoming skin. They induce the differentiation of this neural plate and, subsequently the formation of the entire central nervous system. So from that point of view I think we can all thank our noggin and chordin for giving us a brain and a spinal cord. One last inductive signal I'd like to just talk through is one that has perhaps the most memorable name of all especially those of you that have some history in video gaming. This inductive signal is called SHH, or Sonic Hedgehog, and Sonic Hedgehog is a protein hormone that interacts with receptors that are bound to the surface, and its receptor is a protein called patched that interacts with a protein called smoothened, and these interactions will go on to activate a series of transcription factors that were originally identified in brain tumors or gliomas, and when. Sonic Hedgehog interacts with patched in the presence of smoothed, what we find is a switch in the transcription factors that are regulated within the cell. And, specifically, this Gli1. becomes induced, and it binds to DNA, and modulates gene expression. This Sonic Hedgehog mediated signaling pathway is critical for the proper closure of the neural tube.
