Transcribed by Vandeep Bagga

March 26th, 2014

Craniofacial Biology Lecture 7 Prenatally Craniofacial Development by Dr. Wishe Slide 1 Facial Development 3 Dr. Wishe Before I start todays material, which deals with the nervous system, as I was listening to his talk, I realized that I didnt fully cover certain things in my lectures. We spoke about the development of the face and the nose but I dont believe that I actually told you what the various processes give rise to. Other than the two medial nasal processes joining together forming the intermaxillary segment. And the rest of the nose I just forgot about. The lateral nasal processes actually forms the wings or alar of the nose. And the frontal nasal prominence actually forms the part of the nose that im pointing to, which is the bridge. So in reality, 5 different processes give rise to the nose. So as a result, as you think about this and the various defects, especially the last one that he showed, there is quite a bit involved in this developmental process business. Slide 2 Figure 6.1 Day 16 Embryo Primitive Streak Dr. Wishe Here we have some pictures of your developing germ disc, and originally the disc is straight and it consists of 2 layers. And what were looking at in blue represents the epiblast layer and there should be a layer underneath called the hypoblast. That is your bilaminar germ disc. What happens in the caudal part of the disc is that you have mitosis of these epiblast cells, lets just draw a simple diagram, it is originally straight and then you have these epiblast cells giving rise to more and all of a sudden you wind up with, lets say two folds, and thats what youre seeing over here and in here. And in between the 2 folds is the formation of the primitive streak. So this would be the primitive streak. With continued migration and mitosis of these epiblast cells, the cells now begin to go up this ridge and migrate inward through the streak itself. The same thing happens at the cephalic end of the primitive streak, which is known as the primitive node. And the difference between A and B is just two days of growth, so this germ disc is lengthening, probably getting a little wider, but it is still a flat disc. Slide 3 Figure 17.1 (18.1) Neural Tube Dr. Wishe then what happens at the cephalic end of the embryo, you have another set of folds developing essentially the same diagram that I showed you previously, and it looks something like this. And these are called your neural folds. The indentation, the bottom of the indentation is your neural plate, and the groove itself is the neural groove. This is where you are going to get the formation of the nueral tube, which gives rise to your central nervous system. So what were looking at at this particular point is not much of a folding yet, just a little bit, and you essentially see the neural plate. Moving on to diagram B, you get the impression that this part of the embryo is now beginning to extend upward giving you the impression that a fold is forming and on each side you get the neural fold, in other words, these structures. This is still the neural plate. And this area will eventually develop into a tube. So thats the neural groove. And while were looking at the picture, you can see these little segments, and those are the beginning of the formation of your somites, 1

Transcribed by Vandeep Bagga

March 26th, 2014

which gives rise to various structures. And theres a side picture here, which you might as well look at, most probably a mouse embryo, but its pointing out to you the areas where the various parts of the brain will form. F stands for forebrain, M for midbrain, and H for hindbrain. The forebrain is also known as your prosencephalon, and will eventually give rise to the telencephalon and diencephalon. The M is your midbrain, which is also known as your mesencephalon. And that tends to be the least developed of all the portions of the brain. And H stands for hindbrain, also known as rhombencephalon. And the rhombencephalon will form or divide into 2 parts, a met and myelencephalon. And the metencephalon forms the pons, cerebellum, and the mylencephalon forms the medulla oblongata, which then continues down as your spinal cord. So initially, and this is early on in development, like 18 days, 20 days or so, youre getting 3 bulbous projections representing the 3 subdivisions of the brain starting very early. Everything starts early in your development process. Slide 4 Figure 17.3 (18.3) Neural Tube Dr. Wishe little later on in development, a day or two later, now you definitely see the neural folds and the folds are coming close together. Eventually youll have something that looks like this, and that separated little circle represents what was this area, the neural groove, and when it delaminates or separates from the surface ectoderm, its the neural tube. The two pictures on the bottom are showing you that the tube is wide open and as long as this tube is wide open, fluid flows in and out of the tube. Anyone knows where the fluid comes from? What's sitting on top of this structure? Amniotic sac. And the amniotic sac is filled with fluid. So as long as the tube is open, fluid will pass back and forth. And you know this is a later picture, not only because of the advanced development of the tube, but youll see in this particular area, the tube is beginning to seal up. And the sealing up takes place in the area of the back, the neck itself. And of course these little segments, your somites, are increasing in number. Diagram B is around day 25 and it shows you that the complete tube has sealed except at the anterior or cranial portion, and the posterior caudal portion. So on day 25, the cranial anterior neuropore closes up, and around day 28, the caudal or posterior neuropore will close up. And at that point in time, the neural tube is completely enclosed and you will no longer have, um, amniotic fluid passing through. C represents what is happening in an actual picture, again of a mouse embryo. But C is an earlier stage of development than B and in fact, C is more like diagram A. Slide 5 Figure 19.2 Neural Tube Dr. Wishe and this is what I drew earlier, but what I didnt point out at that time is the presence of the notochord. The notochord has been referred to as a primitive axial skeletal system, but it really isnt. Anybody remembers what the remnants of the notochord give rise to? How come he got some response from you and Im getting zip? Ok the remnants of the notochord actually form the nucleus pulposis, and then fibrocartilage forms around that forming the annulus fibrosis and then nucleus pulposis plus the annulus fibrosis gives rise to your intervertebral disk. So thats a major role of the notochord. Not skeletal support. The major role of the 2

Transcribed by Vandeep Bagga

March 26th, 2014

notochord, Im sure Dr. Saint Jeannet covered this, however, he did give 3 lectures in 1 day and I understand the audience was kind of sparse in that point of time, because you had the midterm in basic tissues and neuroscience the following day. Im not sure, did he say there were 5 people in the 3rd session or not? So you got a bit of catching up to do, hopefully you did that on the general embryology, because this is all on the quiz next week. And by the way, as you look at the craniofacial schedule, it tells you that the quiz in this course covers up to lecture 3, which is today. Ive changed my mind about that, and Ive covered all the material plus my little insert today for Monday. So it going to be really be up to the end of lecture 2. And not 3. And knowing the class, most of them not being here, I better send out 3,000 emails to reinforce that. We have a problem with, I remember 1 of the lecture quizzes, the class was unsure what was on it, I think it might have been the first one. And I eventually sent out 1 email, 2 emails, and I began my lecture reinforcing it. At the end of my lecture, 1 of you, not necessarily those that are present, came up to ask me what is on the lecture exam. *sigh* Anyways, a second important function of the notochord, is that it activates or stimulates the beginning of the formation of the nervous system. And what it does it activates this surface ectoderm, stimulates it to produce more cells, mitosis, and as a result you get the formation of these 2 neural folds. B shows you the neural folds coming closer together, and I threw in an additional diagram earlier that looked something like this, just to show you the folds are closer and closer together. And finally in diagram C, the ectoderm really joins up to this part of the ectoderm, and this little U shaped tube detaches. So here you have the rejoining of the ectoderm, and now you also have the presence of a separate tube, your neural tube. And I said before, its going to give rise to your central nervous system. You will also notice those little brown areas, well developing off the ectoderm is going to be a special group of cells called neural crest. And I refer to this, and I'm sure JP whos Dr. Saint Jeannet talked about it as well. And as the folds come closer together, so do the 2 clumps of neural crests. And when the 2 folds seal together, and you have your neural tube formed, these 2 clumps join up and also detach from the ectoderm and form this region known as the intermediate zone of neural crest. And then that zone sort of fragments, segments, and youll get these segments going around the neural tube itself. Amongst other things, this neural crest will form mesenchyme associated with the head and neck. So all the connective tissue from the head and neck originates from neural crest. Whereas below the neck, the somite will give rise to, amongst other things, mesoderm, which forms mesenchyme and the rest of the body. In addition, the neural crest will give rise to your various ganglia associated with cranial nerves 5, 7, 9, and 10. And it forms the adrenal medulla. In organ systems, they will talk about the adrenal system. The adrenal gland is like 2 of rooming together. There's an adrenal cortex, and an adrenal medulla. The adrenal cortex is related to metabolism of carbs, proteins, and lipids, and is really derived from mesoderm. And the adrenal medulla actually derived from this neural crest area. Slide 6 Figure 18.2 Neural Tube Dr. Wishe and this is the picture thats in your book, the other 1 is an older version. And basically its showing you the same thing, different colorations, and what you 3

Transcribed by Vandeep Bagga

March 26th, 2014

see in red here represents the formation of your somites. The light blue is neural crest, and here obviously, youve had the separation of the neural tube from the ectoderm, as well as the neural crest, and between B and C you will see arrows indicating that the neural crest has fragmented or segmented. And youll see these little gray circles or light blue circles indicated that fragments of this neural crest give rise to your various ganglia and here are more fragments descending to give rise to your adrenal medulla. Slide 7 Figure 18.4 Brain Development Day 28 Dr. Wishe so we spoke early of the development of the brain, first into 3 general components, forebrain, midbrain, hindbrain, and then the hindbrain really differentiates into 2 other parts, metencephalon and mylencephalon. What I didnt mention at that time is that each of these components develop a space called a ventricle. So the telencephalon, which is what were seeing in this particular picture. In fact, well just draw a line across here to indicate that that is the forebrain. Ill draw a line over here, midbrain, and thats hindbrain. So this is the telencephalon and what youre seeing here is 1 of the ventricles. So youre going to have 2 ventricles form, right and left. And this is the part of the brain that eventually becomes the cerebrum. Then as we go into the diencephalon, which is down in this neck of the woods, it gives rise to a number of components, and well get back to that momentarily. And there's a ventricle in there, a 3rd ventricle. The midbrain has a structure called the aqueduct of Sylvius. The hindbrain has a space and thats ventricle 4. And so you have the cerebrospinal fluid that is being produced passing from ventricle 1 and 2, into 3 through the aqueduct of Sylvius, and finally into the 4th ventricle. Thats the normal thing. But certain things can go wrong, and well see that in a later picture. Slide 7 Figure 18.5 Brain Development Day 32 Dr. Wishe here were having further development of the brain and now the various components are being outlined, telencephalon, diencephalon, mesencephalon, metencephalon, and mylencephalon. In anatomy they did speak about development of the brain and Dr. Saint Jeannet spoke about it in early lectures of neuroscience. So I'm not really repeating development of the brain, I'm just doing it in a general fashion. And its going to lead me into defects that can go wrong. So if we backtrack now through the various parts, the mylencephalon as I mentioned earlier, forms the medulla, and in the medulla you have columns of motor neurons. And for the most part, these are associated with the various eye muscle, such as you occulomotor, trochlear, thats 3 and 4, 6 is the abducens. And there are some motor neurons also dealing with cranial nerves 9 and 11. So these are all muscles involved in the functioning of the eye, the movement. And there are some motor neurons located in here, which play a role in controlling the striated muscle of your pharyngeal arches, as well as the smooth muscle of various tracts like your GI system, your respiratory tract, etc. The metencephalon contains the cerebellum and pons. And the cerebellum you should remember is really your coordination center, for posture and movement. Pons is defined as a bridge. So the pons is a bridge between the midbrain and the hindbrain. And so youll have nerve fibers passing from the cerebrum down to the 4

Transcribed by Vandeep Bagga

March 26th, 2014

posterior part of the brain, where the cerebellum is located. Mesencephalon is just, youll have neurons there again involved with eye musculature, as is the most primitive part of the brain. The diencephalon is a rather important part amongst other things, it gives rise to the optic vesicles, which give rise to your eye. And next time, well talk about eye and ear development. In addition, it forms the hypothalamus and thalamus. And this is a regulation center for various visceral functions like digestion, sleep, body temperature and emotional behavior. And there's still another structure that develops off the diencephalon and thats the pineal gland. And thatll be discussed as well as the hypothalamus in the endocrine system. But the pineal gland responds to light and dark. And you act differently, you have a different emotional reaction to light and dark. And frequently youll find calcified deposits in this brain and itll show up on an X Ray. Now the telencephalon is essentially your cerebrum. You have your 2 cerebral hemispheres with the 2 ventricles. Slide 8 Figure 18.26 Pituitary Dr. Wishe Ah yes, I forgot about this. The pituitary also develops off the diencephalon. And again this will be discussed in the endocrine system, but essentially, here's your folding of the embryo, and its obvious that this is going to be the brain and this down here will give rise to your spinal cord. There are 2 components that go into making up the pituitary. 1 is the, I guess this is sort of reddish in color, is an invagination of the oral ectoderm pushing in to the developing embryo. And it is pushing in, literally, off the oral cavity, and as it pushes in, it creates a space called Rathkes pouch. At the same time, you see this little blue thing coming off the brain, thats the infundibulum, which is also ectodermal derived and the two grow and extend and eventually join. That gets larger, and so in this last diagram, you see the various components of the pituitary, essentially off this Rathkes pouch, youre going to get the anterior lobe. Itll give rise as well to the pars intermedia, which is between anterior and posterior lobes. And this pars tuberalis, which surrounds the infundibulum stalk. And then the pars nervosa actually is a derivative off the infundibulum. And the pituitary gland is very important in relation to secretion of hormones and it in turn is controlled by the hypothalamus. And so there is a feedback mechanism that exists. Something happens in the body, your not producing enough thyroid hormone, your hypothalamus picks this up, sends out a certain factor to the pituitary gland, and this factor then stimulates the pituitary gland to secrete another stimulating factor, which then goes to the thyroid gland itself, causing it to release thyroid hormone. I'm not mentioning the names of the factors because it doesnt help us in our discussion at all. But they will all be discussed in detail in organ systems. Slide 9 Figure 18.28 Gyri and Sulci 7 & 9 Months Dr. Wishe so back to development of the brain, its just like we start off with a flat disc for the embryo and it begins to fold or flex because it cant grow straight out, a similar process happens in terms of the brain itself. At this point in time, you see the various lobes, frontal, parietal, temporal, occipital lobes, a separation in this area, which leads to the formation of lateral fissure. So how does the brain increase 5

Transcribed by Vandeep Bagga

March 26th, 2014

surface area? Well it does it by forming these sulci and the gyri. So the brain surface was originally smooth, now it becomes very convoluted. And in the process, you are increasing the surface area. Slide 10 Figure 18.14 Action of Genes Dr. Wishe nothing to get spastic about. But genetics is coming into more and more of play in the whole developmental process, so I know JP mentioned a few genes and factors to make you aware of it, so Im just showing you the same thing here. So here's your neural tube, this stands for hedgehog gene. And I'm not going to mention anything else, but different factors play important roles. And while its in the picture, there's your somite, which gives rise or came from the paraxial mesoderm, here's your intermediate mesoderm, and here's your lateral plate mesoderm. The somite breaks up into segments, schlerotome, myotome and dermatome. Schlerotome gives rise to all the connective tissue, soft and hard. The myotome to the associated muscles with the spinal column. And the dermatome forms the dermis underneath the ectoderm, and dermis plus ectodermal or epidermis covering equals skin. Slide 11 Figure 18.35 Skull/Neural Defects Dr. Wishe now for defects. Skull neural defects. A child can be born with just a little opening in the back of the skull. And that is generally referred to as a meningocele. But in most cases, the opening the large enough so that the meninges will protrude through, so this whole thing is actually meninges protruding through. And if you look at the picture of the child, this is exactly the way it looks. The next stage, your meningoencephalocele, you see the purple coming through, and the purple is the brain tissue. And the last case, the meningohydro-encephalocele, the ventricle comes through. Slide 12 Figure 18.36 Meningoencephalocele Dr. Wishe and there's an example of meningoencephalocele. This protrusion is larger than the whole head. Can this be corrected? No, not really. So thats one type of defect. And you got to find something like this also effecting the spinal cord. Slide 13 Figure 18.37 Anencephaly and Craniorachischisis Dr. Wishe here we have some other defects. Youre missing the top of the skull, and if you looked at the brain, whatever brain tissue is left is necrotic, its degenerated and died off. What happened here is that the formation of the calvarium or skull did not go as it should have, and therefore no bony components formed on top, as a result, the developing brain is exposed to the air and completely degenerates, because survival is zero. The absence of a brain is called anencephaly. Whenever you see the use of a in the beginning of the word, it usually means absence. The 2nd term, craniorachischisis refers to what's happening down over here. The neural tube did not close in this region. Here the neural tube didnt close where the top of the skull is. So therefore your whole spinal cord becomes exposed. And again, these 2 do occur together, and the child dies pretty quickly under the circumstance.

Transcribed by Vandeep Bagga

March 26th, 2014

Slide 14 Figure 18.38 Hydrocephalus Dr. Wishe here we have a situation, hydro, usually refers to fluid, and the previous examples when I mentioned the word, the long word, meningohydroencephalocele, the hydro also referred to the fluid which is present in the ventricles, cerebrospinal fluid. What happens in this case, and theyll talk about this in pediatric dentistry, is that the ventricle in the midbrain, which is your aqueduct of Sylvius, becomes blocked, clogged. And CSF is still being produced in ventricles 1 and 2, as well as in the diencephalon, thats 3. So the fluid cannot exit ventricle 3 to get to ventricle 4. So what happens, its like you're pumping up a tire. Here more and more fluid is being released and it cant exit. So what it does do, it pushes outward, thinning out the bone thats forming, the connective tissue, etc. and you can use your imagination that if this continues to go on, the whole thing is just going to burst open. Now in order to correct this, you have to go surgically, remove the fluid, and clear the blockage in the aqueduct of Sylvius, otherwise the same thing is going to happen once again. Slide 15 Figure 17.39 Microcephaly Dr. Wishe now this girl looks pretty normal, and you cant really tell from the picture, but this is called microcephaly. So she has a small brain, which means that the formation of the bones, the junction of the parietal bones occurred too early and when these bones form together too soon, your limiting the development of the brain, there's no space for it to grow into. So you get an underdeveloped brain, and once you get an underdeveloped brain, the child is going to be mentally retarded, there's no way around it. Well talk more about when we do the skeletal embryology. Slide 16 Figure 18.34 Holoprosencephaly Dr. Wishe this is a slightly different scenario, holoprosencephaly, I had referred to a median or a medial cleft of the maxilla, and so did Dr. Lai. And here the defect here is that you are not getting proper development of the medial nasal process because of the lack of proper mesenchyme development and so youre getting not only a little cleft in terms of the maxillary lip, but you're getting a whole area up to the brain which is deficient in the number of cells. So the fact that it goes to the brain, the person is going to be mentally retarded. And may have only 1 cerebral hemisphere, not 2. 1 ventricle instead of 2. And then of course eye development will be seriously defective as well. So this is another type of a situation and if this individual lives, its not going to be very useful to itself or society. Slide 17 Figure 17.15(18.15) Spina Bifida Dr. Wishe I think well stop at this point and then well continue our discussion on Monday with the spinal cord and well lead into eye and ear.