Transcribed by David Landsman Craniofacial biology Skeletal and Muscular Systems, Dr.

Wishe

03/31/2014

Slide 2 Bones of the skull (month 3) Dr. Wishe OK I guess we might as well start. So today we are going to talk about the skeletal system and teratology. You have had information about the skeletal system before from anatomy, and in essence, in basic tissues when we talked about bone, endochondral bone formation and intramembranous bone formation. In essence the skeletal system is derived from paraxial mesoderm, Dr. Saint-Jannet spoke about that, and that gave rise to somitomeres which then gave rise to somites. And your somites broke up into 3 sections, your scleratome, your myotome and dermatome. And scleratome is responsible for giving rise to all the connective tissue in the back, in essence, the soft connective tissue, the skeletal components, etc. The myotome gave rise to the musculature of the back, like the spinalis muscle, and finally the dermatome gives rise to the dermis of the skin. And the ectoderm forms itself. And then we have the parietal layer of the lateral plate mesoderm -- or the somatic layer -- some people like to use that term, and neural crest. So there are different sources in terms of what forms the skeletal system, etc. Now when you look at a skull, this is a picture of a skull, it is supposedly 3 months old. Essentially you will find 2 components that develop and you only see one component in this picture, what you really see here is the neurocranium. And the neurocranium forms via intramembranous bone formation whereas the base of the skull will form via endochondral bone formation; that means the base of the skull starts off as hyaline cartilage. So we are looking at the neurocranium, which is formed intramembranously, and it is referred to as the membranous neurocranium and in essence most of this which you are seeing here really is derived from neural crest and essentially forms the roof and the lateral components of the neurocranium. And as you recall back to basic tissues, intramembranous formation you would start off with mesenchyme in this case derived from neural crest and would give rise to osteoprogenitor cells, then osteoblasts, and the osteoblasts lay down the bone matrix, which was originally non-calcified before it became calcified. The difference about the skull versus the long bones is in the long bones you have a primary and secondary center of ossification. Primary is the diaphysis, secondary is epiphyseal region. When it comes to the skull bones you can have 2, 3, even 4 centers of ossification and just for the sake of illustrating it Im just drawing in these four little dashes to indicate 4 centers of ossification. And each one of the starts giving rise to bone then they all sort of join together and eventually you get your parietal bone, frontal bone, etc. And what is labelled up here is your bone spicules. If you remember, the bone spicules are little pieces of bone that form and then they become larger, they become trabecular, and eventually you will get a whole bone formed. And this is all through intramembranous bone formation. The pictures showing you these areas in black which also is derived via intramembranous bone formation, again from neural crest derivatives.

Transcribed by David Landsman

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Slide 3 Bones of the skull Heres a picture, a little bit later on in development, and it shows you the various bones that form. Its a little bit hard to recognize on this picture but the blue area is part of your face development whereas the brown area has nothing to do with the face but the rest of the skull. And youll see the bones are separated by spaces and within these spaces youll find connective tissue sutures. Slide 4 Skull of a newborn Now this is a nice picture from the skull of a newborn. When the child is born the bones of the skull are not truly joined together by bony sutures. If they were this would leave no flexibility for the brain to develop. And when the brain is finished developing it sends out certain factors which stimulate the skull to continue with their growth and close up the sutures. So what you see in blue represent connective tissue sutures joining the various bones. For instance, here is the coronal suture it separates your frontal from your parietal. If you look at this suture, its the sagittal, separating the two parietals. And this is your frontal suture separating the frontal bones. And I mention those for a specific purpose, which you will see later on. Then you have some larger areas in blue, like this, and they are referred to as fontanelles. And the anterior fontanelle is the largest of all the fontanelles. Theres one a little smaller back here, which we dont have too good a view, the posterior. And then when you look at the lateral skull youll find two other fontanelles, the sphenoidal and the mastoid. And these are wider areas of connective tissue to permit growth to occur. And as you look at this face, this is essentially the face and this is the rest of the skull with the brain. So the face doesnt actually occupy that much face, per se. For the development, you get the formation of the various sinuses, like the maxillary, the frontal sinus, etc. and eventually you get the formation of the dentition. The appearance of the sinuses and the dentition broaden out the face and then the face seems to occupy a much larger area of the entire head region. Slide 5 Base of skull development Here were looking at the base of the skull and whatever you see in blue and, I dunno reddish brown colour, represents the different cartilages. And at one time we used to hold you responsible for the naems of the cartilages but now the books seemed to have eliminated it and we are basically now looking at the names of the bones. The largest bone is the sphenoid and it really comes from 3 different past cartilages. So you had the lesser wing, the body of the sphenoid, and then theres the greater wing. And when you look in this particular area, this opening which is the sella turcia where the pituitary develops. So part of the sphenoid over here surrounds the superior part of the sealla turcica and youre getting alittle part of the body from this brown region, which is the posterior region around the sella turcia. Whatever is in blue is definitely derived fro neural crest. What you see here in brown really comes from your paraxial mesoderm, thats why the difference in colour.

Transcribed by David Landsman

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Slide 6 Fig. 8.7 Anencephaly Meningocoele So the sutures are around for quite a while, and if youve ever gone to your mother to the pediatrician with your kid sister or kid brother and the pediatrician looks like he or she is scratching the babys skull, thats not whats happening. The pediatrician is feeling for the anterior fontanelle, and if he finds something hard it means there is something wrong. It means the anterior fontanelle has actually sealed up. But as long as it feels soft, youre ok. They dont necessarily feel for all of them but just doing the anterior is good enough indication that everything is ok or not ok. If these bones seal up too soon you get improper formation of the brain. The brain doesnt have enough room to fully develop so youre gonna get a microcephaly type scenario and the individual will be retarded. It depends when the bones actually seal up. All the sutures dont seal up at once, they gradually do that as the brain releases these stimulating factors. Into the teen years you even have some sutures partially open, thatjs to allow additional growth if necessary. But by all rights, by the time the child is 7 years old, the brain is pretty well developed. It doesnt process all the information thats possible, its a learning process to get to that point. Back to slide 5 - Base of skull development Actually, what I should do is return to [slide 4], we are not quite ready for that picture yet. So the neural crest has been referred to as giving rise to the precaudal chondrocranium thats superior to the sella turcica. And the paraxial mesoderm actually gives rise to the caudal chondrocranium. This is the precaudal and this would be the caudal. Everything in blue comes from neural crest as I mentioned, everything in this brown color comes from the paraxial mesoderm. And as you look at the visceral cranium, thats where you have your bones actually, which is what you see in this picture [on slide 1]. You have the maxillary process, the mandibular process forming, the maxillary process of course gives rise to the zygomatic bone, the maxilla, the premaxilla, part of the temporal bone and the mandibular process essentially forms the mandible. And we spoke about the mandibular process or prominence having the presence of Meckels cartilage. And then from the second arch, the hyoid arch, you get Reicherts cartilage. Between the combination of two you eventually get the formation of the ear bones, the malleus, the incus and the stapes. And by the way they are the first bones in the body to develop. Slide 6 Fig 8.7 Anencephaly Meningocoele Now we come to this picture. Weve seen this picture, maybe not this picture, but pictures similar to it and there are conditions that unfortunately develop. The top picture is anencephaly and I told you that the letter A means missing. So you are missing the top of the skull the calvaria of the skull, exposing the underlying neural tissue, which becomes necrotic and sort of just dies. Survivability here is actually zero. Another term that you may come across, Ill just mention it to you, called cranioschisis, and cranio means cranium, the cranium vault, um the bones fail to seal up at all. So you get lack of absence of the formation of the parietal bones, and if they do form they are minimal.

Transcribed by David Landsman

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And in the bottom picture, the meningocoele we spoke about. And there are openings in the back of the skull, could be just a little opening, could be a little larger, and whenever you see the prefix meningo that means it involves the meninges. And the meninges sort of expand out into this little sac like structure. And it could even blossom out more, besides the meninges, you could have the meninges plus the brain tissue. And finally the last condition you could have the meninges, the brain tissue and the ventricles bulging out. And those are sort of difficult to correct. Slide 7 Fig. 10.8 Anencephaly meningocele Heres a perfect example. We saw these previously, and this is your anencephaly, you are missing the whole top of the skull and the brain tissue is sort of gone. And heres the other version of the meningocoele, now the fact that this is so large it might be a meningohydroencephalocele, hydro means fluid. So you probably really have meninges, brain and ventricular fluid (cerebrospinal fluid). This bulge is larger than the head. Under these circumstances, the survival rate is also really zero. Slide 8 Fig 18.37 Anencephaly and Craniorachischisis And here are another two versions, this picture we saw just previously and its turning the infant around so you see here massive neural tube defects. The whole neural tube in essence is wide open and the whole spinal cord will be wide open. Thats your craniorachischisis, it involves the neural tube in the back as well as the absence of real functional brain tissue. Slide 9 Fig 10.5 Skull of a newborn And this I just show a refresher because that leads us into the next condition, your craniorachischisis, where the sutures and/or fontanelles close too early. Slide 10 - Craniosynostosis So here are examples of three children. And picture in A, this child has a pretty tall tower and the face is somewhat on the narrow side so that means the sutures that were up here closed to soon and that sort of narrows the size of the whole face. And the only place that you can have growth is upwards. This one [B] is hard to tell, its a side view, but it also looks like there is a high tower. And [picture C] is completely different, you dont have a high tower, but its like the face has been compressed down. So that means all the sutures on the side closed too soon and the brain cant expand upwards. Slide 11 - Craniosynostosis Some diagrammatic versions. These two show your high tower, there are more specifics but we are not getting involved with that. Its just that certain sutures closed too early. This one is where the side suture closed to soon, she has sort of a squat looking type of face, and this one is sort of in between, ore normal in appearance than any of these three. Now if the doctor discovers that the sutures are closing or closed in the child they can surgically correct it. And you can open up the suture but thats generally not good enough because the sutures will close back quickly. So what they generally do is remove part of the bone on each side of the 4

Transcribed by David Landsman

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suture. So if this is the suture and well say this is the bone, they are gonna open up an area like this, the bone will regrow back, itll take time, but the important thing is that it gives the child a chance for brain development. Slide 12 Vertebral Column Before we get into that, um, there are two conditions which youve seen, and they are completely opposite. Chondroplasia thats where you have a pituitary tumor, too much growth hormone, too much thyroid hormone being produced and this generally affects the entire body. So the individual has a large head, large body, large hands and I gave two examples in a previous lecture, like Andre the giant, the wrestler, or the guy that played jaws in James Bond. So they have excessive growth. And the opposite of course is something like dwarfism, where all that growth is reduced in terms of the long bones the growth centers shut down and you cant get any further increase in growth of the long bones. And the same thing occurs in terms of the skull. But the skull and the rest of the body are all in proper proportion to one another, its just not a normal sized individual. And of course there are all sorts of signalling factors, like fibroblast growth factors, etc. which play a role in all these formations. We are looking now at development of the vertebral column. You remember this structure, the notochord, which was supposedly playing a role as a primitive axial skeleton, it doesnt. the important function of the notochord is to stimulate the function of the neural tube. Then the notochord disintegrates and you have remnants of the notochord which give rise to the nucleus pulposus. Which is part of the intervertebral disc, and then surrounding the nucleus pulposus youll get your annulus fibrosus, which is your fibrocartilage and these two components equal the intervertebral disc. But something else also happens, the blocks of tissue that you see here represent actually your somites. Which give rise to scleratome blocks and part of the scleratome will form your skeletal elements. Attached to each scleratome block youll see these little kidney shaped structures brown in color and you can see this little yellow area between the two. Well, these kidney shaped structures represent your myotome segments. And the little yellow structures represent the nerves. And then between each scleratome block youre gonna get an area in between with some mesenchyme called intersegmental mesenchyme with a little red structure feeding into it. Thats a development of your vasculature. This also shows you a downward growth of arrows, what the diagram is trying to tell you is that the caudal part of one scleratome block grows in an inferior position and joins with the cephalic portion of the next block. As a result, you get the formation of a new block. And thats what essentially youre seeing over here [B], and these new blocks are called precartilaginous vertebral bodies. But at the same time, notice that the myotome block and the nerve and the vessels have now shifted position. So now the myotome segments are associated with the intervertebral disc, and so is the nerve, and the vasculature now feeds into the precartilaginous vertebral body. In picture A, if everything stayed the way it was, you wouldnt really have movement in the back. Youd literally be frozen in shape. But by shifting of these components now associated with the intervertebral disc, youre able to bend and twist whereas before you couldnt. You literally had a frozen vertebral column. And then in diagram C, it shows you the more mature structure and precartilagnious vertebral 5

Transcribed by David Landsman

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body gives rise to the vertebra and this becomes your fully mature intervertebral disc. And then of course there are these muscle elements which connect one vertebra to the other. Which gives you the degree of flexibility you need for purposes of movement. So things can go wrong, as with any place. Coming off the vertebra are your spinal processes which go around, and surround, then fuse together, and protect the underlying spinal cord. In addition you have these transverse processes coming off the vertebra which now wrap around the body and give rise to the rib cage. So the rib cage is really derived off the transverse processes of the actual vertebra. Sometimes youll get a condition where you only have proper formation of one side of the vertebral column. So if you see someone sort of walking like this there is a problem with the vertebral column. The vertebra are fused in one spot and sort of separated in another. So the person cant possibly straighten up. Well, Dr. Davidson gave us a CCP in basic tissues in gingivitis. I dont know if you paid attention to him but youd see that he has actually two curvatures. One over here and another one in his neck, he cant pick his neck up. Thats because he had problems with the intervertebral discs and the two vertebrae are fused together, once you fuse two vertebrae together you lose your degree of movement. Theres nothing you can do about it. So all sorts of things happen. Slide 13 - Chondroplasia And this is your chondroplasia, or achondroplasia, whatever you want to call it. This is the formation of the dwarf. So you can see the body proportions are correct for this individual. A condition associated with your dwarfism is the bowing of the legs, so the bones arent forming exactly as they should be and they sort of bend in. this has nothing to do with pituitary tumors. A pituitary tumor just causes an enlargement by stimulating the growth sensors. So a more appropriate term might be achondroplasia, I think I mentioned it before but not necessarily in this context. So theres achondroplasia which is sort of like a hypo-development, versus a hyperdevelopment which is for a pituitary tumor. Slide 14 Limb Bud development A little something about limbs. Weve seen this pictures before for other purposes. The disc starts off straight and then you have flexion occurring and you get this bending. During the third week of development, a lot of good stuff is happening, and Ill show you a little figure in the next part of the lecture which shows you what systems are developing during what period. So these little bulges here are your superior and inferior limb buds. And a bud is like a balloon, when you blow up the balloon this part expands. The same thing happens with the development of the dentition. This bud then sort of changes shape and begins to look almost like a pingpong paddle. As you look at this ping-pong paddle you can see little darkenings inbetween. Those little darkenings are mesenchyme degeneration and so you go from a structure that looks like my hand and by the time youre through you get the formation of the digits, whether its the toes or fingers is irrelevant. And C shows you much more highly developed scenario and you can see the fingers and the toes. 6

Transcribed by David Landsman

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Slide 15 Apical ectodermal ridge Heres a limb bud, its going to be surrounded by ectoderm, and you can find mesenchyme in the body of the limb bud. This mesenchyme then stimulates the surface ectoderm which thickens and forms this little area called the AER (Apical Ectodermal Ridge). And heres another view, this is the apical ectodermal ridge. Then in turn the AER has a stimulatory effect on the mesenchyme to have further connective tissue stimulation to help form the particular limb. Slide 16 Limb development Those little ping-pong paddle-like structures here are called foot plates or hand plates. And while the limb is developing in terms of its shape, you have mesenchyme inside which is beginning to give rise to your various bones. And of course the bones are forming from a different source, its forming from your lateral plate mesoderm, or somatic layer of that. The splanchnic layer of the lateral plate mesoderm has nothing to do with bones but rather it surrounds individual organs like the stomach to give rise to your visceral or splanchnic mesodermal covering. Its the outer layer, the somatic layer or parietal layer, that plays a role in the development. So everything is happening more or less at the same time. And everything of course is controlled by chains and various factors. Ill just mention one: like bone morphogenic factors, youve heard that in connection with bone. Youll hear it again in terms of formation of dentin, of your teeth, but bone morphogenic proteins induce a certain gene. Your MSX2 gene, might as well get used to it, because it also plays a role in the formation of the teeth. So there are certain similarities, and the similarity we are talking about now is affecting the development of your hard calcified tissue. MSX1 also plays a role in formation of your teeth. And well deal with that when we come to the appropriate area. So going from this stage, we go to B. And you can see that there is a little indentation here, it means the undermesenchyme is sort of degenerating. In here is the indentations that help us form the digits. And again this applies to both hands and feet. Slide 17 Hand development Heres another diagram which shows this a little clearer. Heres your ping-pong paddle showing you regions where the cells are dying, and thats increasing, until finally you get something like that. Now these indentations are not complete. Just hold up your hand, youve got pretty deep indentations separating your fingers. So this is all just progressive work. Slide 18 Hand development days 46 56 And here we have some pictures, which shows you the actual development of the hand and you can see the little indentations here. You count up and you get five fingers. Diagram B, the indentations are a little bigger. Now, between these two fingers and these two fingers, you can see tissue. That tissue hasnt degenerated yet, but a defect that can occur is a webbing defect such that somebody can be born with feet where the fingers are born with webbing in between. That improves your swimming ability, but it doesnt look so great. What it does for the hands is gonna limit the motion of the fingers and what you can do. Why it is an advantage in terms 7

Transcribed by David Landsman

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of the feet, think of a duck. You can see there are three hard components and there is webbing between, that is how the duck makes its way through the water. So thats an advantage there. Slide 19 Limb defects Amelia Phocomelia Now these are other defects which affect one up to four limbs. And the first one is your Amelia, A means absence. And if you look at your individual, for all practical purposes, this limb does not exist. And this was caused by taking thalidomide, women get nauseous during pregnancy and they cant sleep. Thalidomide was given to them and no one realized it affected limb development. So an individual could be born without any limbs altogether. Theres a condition call meromelia, mero means partial so youre missing part of a limb. So lets say the upper extremity, you have the part that goes to the elbow and then youre missing the rest of the limb. And this could happen to one limb or a number of limbs. And the picture on the right that you are seeing here is called phocomelia, and in essence you have the hands and the feet developing but you dont have the limb in between, so the hands and feet are attached to the body by a short little bone. Slide 20 Polydactyly, syndactyly, cleft foot So those are other conditions. And most of these types of conditions happen to be caused by teratogens. A teratogen is something that leads to abnormal development. Here we have two different scenarios, the top picture shows you polydactyly. Poly means many. And if you count the digits, there are six digits. Cases of up to eight digits have been reported. Now in this case you have fully functional fingers so your manual dexterity should be improved. I would imagine an individual with six digits would make an excellent baseball pitcher. Good grip on the ball. On the other hand, we look and B and C, normal thumb normal pinky, and you can tell there are two more digits here but theyre fused together and youre missing one. This is a condition known as syndactyly, youre missing. C also shows you a version of syndactyly and this condition here they call it a cleft foot. But another name is lobster claw. So in essence if you look at my hand, this is your lobster claw, and it could apply to your feet or your hands. Slide 21 Digit development Here again we see the polydactyly, but it is also showing you on the side, this is part of the limb bud and the mesenchyme cells here are stimulating the ectoderm, thats the apical ectodermal ridge, the thickening, and then the AER stimulates the undermesenchyme to help form the soft connective tissue. Slide 22 Digital defects Another picture, again showing you the formation of your hands and your feet. So here we have five digits, I dont believe these are fused, they are probably just overlapping, but the digits are small. In this scenario [B], you look at the left hand and you have 3 normal digits, these two are fused together. And if you look at the 8

Transcribed by David Landsman

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right hand you only have two normal digits and these three seem to be fused together. This one [C] is also a situation where you have short digits. We could probably take this as your normal view, although I would probably like to see longer digits, and this is your micro view, shorter digits. And here of course is your lobster claw. Although you have this claw like structure, individuals with this on their feet could technically balance themselves and walk. Slide 23 Somite development OK. In terms of the ribs, we already mentioned that they came from the transverse processes. Everything came from your somites which came from your paraxial mesoderm. In terms of your sternum, which develops in the midthoracic region, the sternum comes from your somatic, your parietal lateral plate mesoderm. And between the sternum and the developing ribs, for the true ribs youll have your costal cartilages, hyaline cartilage formed, and thats the attachment point. And there are two fixed ribs attach to the regular ribs and then you have floating ribs where they are not attached to anything. What we are going to talk about now is a little bit about muscular development. So here again we go back to our friend the somite and the ventral and medial parts of the somite forms the scleratome and thats where we get a lot of the structures we just talked about. And the dorsal part of the somite forms a dermomyotome, thats this area better seen down on figure C. and then the dermomyotome splits up and you get a myotome and finally a sclerotome. Again, the sclerotome forms the dermis and the myotome forms the associated musculature with the spinal column like the spinalis muscle. Slide 24 Gene regulation And this is nothing to get spastic about, but like Dr. Saint Jeannet and I, we mention just a few things involved. Hes more liable to ask you these names than me. Hes big on hedgehog gene and noggin. And all these other things like PAX3, NT-3 are all genes. Here you have the dorsal part of the neural tube being affected by bone morphogenic proteins. The ventral part of the neural tube and the notochord have genes. So they all taking their effect on the sclerotome, the myotome and dermatome. So obviously Im not gonna ask you any of that. Slide 25 Muscles Now as we look at the somites, and thats essentially what youre seeing here. But this particular diagram is more interested in your myotome portion and not the scleratome and not the dermatome. So for every somite that you have, theres 44 pairs, youre gonna get a myotome. And the first few myotomes play a role in the musculature up here and all these myotomes play a role in the musculature below the neck region. And if you take a particular myotome, lets say what are these? Say its a cervical myotome. And you look on the diagram on the right, you see that myotome splits into two components: a dorsal and a ventral component. The dorsal component is called the epimere, thats where you get your extensor muscles forming. And these are the muscles that are located in the vertebral column. The 9

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ventral component is called the hypomere and these are your flexor muscles of the spine. So depending on where you are looking at, they are gonna give rise to different musculature. So if you look at the hypomere, those in the cervical region, youll find that they will give rise to the scalene muscles, the geniohyoid, the prevertebral muscles. If you look in the thorax area, they are gonna give rise to all the intercostals, external, internal, innermost. And if you look in the abdominal area, the abdominal myotomes are going to form your oblique muscles. Remember those? The external and internal oblique, and theres this old guy called the transversis or transverse abdominal muscles. And then there are myotomes going further down but we wont get into that. That was the old way of looking at things, they have a new type of nomenclature which I dont see what that does for us. So instead of using that term epimere, they use the term primaxal domain and instead of hypomere, abaxal domain. And where that comes from, the primaxal domain literally wraps around the neural tube. Well sure its going to wrap around the neural tube because you have your spinal cord surround by your vertebra and youre gonna have nerve plexus there. Whereas the abaxial domain really is derived from your paraxial mesoderm, specifically your parietal or somatic layer. Also, neural crest plays a role in the formation of your epimere. So it doesnt matter how we look at it. If you get a question on the boards like this, I have no idea which system they are gonna go to, just keep in mind the epimere is your primaxial component and the hypomere is your abaxial component. And while we are looking at this picture, coming off the hypomere you can see these muscles going into the limb, so therefore the muscles of the limb come off of your lateral plate mesoderm, the somatic/parietal layer. Slide 26 Muscle development This just shows you a little further elaboration of what we saw in the previous picture. Its just trying to show you the layer effect that you could get, say, from your various oblique muscles or your intercostal muscles. Slide 27 Limb development I love this picture, especially C, it looks like a little devil. And what this is showing you here is the formation of your superior limb. C stands for cervical and T for thoracic. So the musculature is being derived from your lateral plate mesoderm in the cervical and thoracic regions. And heres a further elaboration showing the inferior limb, again this is something you dont have to know, just know where the muscle comes from. So the numbering is just referring to which part of your myotome section this is all being derived from, where the lateral plate mesoderm fits in, thats all. 10 minute break.

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