Chapter 16 Axial Musculoskeletal Development PDF

2024 CHAPTER 16 Chapter 16 - Axial Musculoskeletal Development Key terms and concepts: Paraxial mesoderm Somitomeres Somites Somitogenesis Segmentation clock Sclerotome Sclerotome resegmentation Dermatome Myotome...

2024 CHAPTER 16 Chapter 16 - Axial Musculoskeletal Development Key terms and concepts: Paraxial mesoderm Somitomeres Somites Somitogenesis Segmentation clock Sclerotome Sclerotome resegmentation Dermatome Myotome Endochondral ossification Ossification centers Vertebral/spinal column versus spinal cord Vertebra, hemivertebrae, block vertebrae Hox genes Intervertebral disc, nucleus pulposus, notochord Annulus fibrosus Neural crest, dorsal root ganglia, motor nerves Learning objectives: By the end if this unit you should be able to: 1. Understand the embryonic origin of the vertebrae. 2. How do ossification centers play a role in the formation of bones? 3. What is the role of Hox genes in development of the vertebral column? What is the role of Sonic hedgehog? 4. Understand the relationship between segmentation of the somites and segmentation of the vertebrae. How does this impact the eventual anatomy of the vertebral bodies and associated muscles? 5. Know the components of the somites and their derivatives. 6. Understand the mechanism of positioning of the spinal nerves and the dorsal root ganglia relative to the vertebral bodies. 7. Explain the embryonic origins of the intervertebral discs and what happens to the notochord in this process? 8. Explain the embryonic origins of the various developmental defects described in the notes. I. Differentiation of Mesoderm A. Let's step back for a moment and review the formation of mesoderm. The mesodermal layer formed by cells that pass through the primitive streak is initially arranged as a thin sheet of loosely organized cells to each side of the midline. A good histological description of this tissue is mesenchymal, which applies to loose connective tissue with a lot of extracellular fluid and matrix. Soon, however, changes occur in this initially uniform layer. 1 2024 CHAPTER 16 B. The intra-embryonic mesodermal cells closest to the midline (just lateral to the notochord) proliferate and form thickened columns called paraxial mesoderm. At the lateral margins of the disc the mesoderm remains thin and is called lateral plate mesoderm. The mesoderm connecting the paraxial and lateral plate regions is the intermediate mesoderm. Together these three regions form the intra-embryonic mesoderm, which is continuous with the extra-embryonic mesoderm at the edges of the embryonic disc. II. Differentiation of Somites A. At the same time that the primitive streak regresses caudally, laying down the notochord behind it, the paraxial mesoderm segments into somitomeres, which are first seen at the cranial end of the embryo, with new ones forming farther caudally as time goes on. 1. The original paraxial mesoderm is mesenchymal and appears homogeneous. As time progresses, the cells become organized into a series of concentrically arranged clusters called somitomeres. The division between adjacent somitomeres is subtle. B. The first several pairs of somitomeres will disperse within the head region. We will discuss their fate later. Beginning with approximately the 8th pair and moving caudally, somitomeres will differentiate into more clearly defined somites. The somites form sequentially in from cranial to caudal. CONCEPT: Segmentation The formation of somitomeres and then somites in a repeated pattern from cranial to caudal is the first indication of segmentation in the embryo. Somites will influence the subsequent patterning of all the other segmented tissues such as spinal nerves, segmental blood vessels and vertebrae. 1. As cells of each somite unit condense, clefts form cranial and caudal to the unit, making each somite easily visible. Interestingly, the amount of time it takes for a pair of somites to develop is consistent and characteristic for each species (90 minutes in the chick, 120 minutes in the mouse). This is used experimentally to determine the age of embryos (as in, “I see this pig embryo has 11 pairs of somites, so according to the chart it must be 15 days since fertilization!”). 2  2024 CHAPTER 16 Somite formation requires the coordinated action of at least 300 genes, many of which are expressed in a cyclic fashion. These waves of gene expression, known as the segmentation clock, occur with the same periodicity as somite formation. Before this process begins, however, opposing gradients of FGF and WNT signaling molecules and retinoic acid are present in the presomitic paraxial mesoderm. These gradients are then superimposed with the oscillatory expression of Hes7 and members of the FGF, WNT, and NOTCH signaling pathways. Cranial-caudal regionalization of the future vertebra is determined by nested expression of Hox genes in the somites, reflecting their linear arrangement along the chromosome (as we discussed in Chapter 7). C. Soon after its formation, each somite differentiates into three histologically different parts, each having a different future. This differentiation is triggered by signals from nearby tissues such as the epidermis, neural tube, lateral plate mesoderm, and notochord. Numerous different factors act as signaling molecules in this process. One of them is an old friend: Sonic hedgehog (Shh) from the notochord plays a role in the process and is important in sclerotome formation! 1. Sclerotome a. Differentiates into several types of connective tissue, including cartilage, and bone of the axial skeleton. The ventral portions of the sclerotomes will migrate medially to surround the notochord, which induces them to form the vertebral bodies. The dorsal portions will surround the neural tube, and are induced by the nearby surface ectoderm to form the vertebral arches. 2. Dermatome a. Cells migrate just under the ectoderm to form the dermis. They carry with them sensory nerve fibers 3. Myotome a. Cells migrate to form skeletal muscle of trunk and limbs. Each myotome is associated with its own segmental nerve which will follow the migrating muscle cells to their proper location (e.g. proximal cranial forelimb = biceps). III. Axial Skeletal Development A. Chondrogenesis and Osteogenesis in General 1. Cartilage and bone provide the structural framework of the body. They both develop from mesenchymal cells which are indistinguishable from each other until they begin to produce the characteristic matrix of either bone or cartilage. 2. Several embryonic tissues, including sclerotome cells, have the ability to differentiate into bone and cartilage. We'll look at other origins of bone (such as in the limbs) in the next chapter. 3. In some bones, such as the flat bones of the skull, condensed layers of mesenchyme differentiate directly into bone (intramembranous ossification). For most bones, however, mesenchymal cells first differentiate into chondrocytes which produce hyaline cartilage models that are shaped somewhat like the eventual bone. 4. The hyaline cartilage models are later invaded by osteoblasts and are replaced by bone in the process of endochondral ossification. Endochondral ossification begins in the primary ossification center. In long bones, the primary ossification 3 2024 CHAPTER 16 centers are in the diaphysis of the bone. Later in development, secondary ossification centers will arise in the epiphyses. Some bones have even more ossification centers all of which must eventually fuse to form the mature bone. For example, the axis (cervical vertebra 2) forms from 5 ossification centers! 5. Undifferentiated but determined cartilage and bone cells (stem cells) remain in the adult (in the perichondrium or periosteum) to provide for repair of these tissues. B. The sclerotome cells of each somite migrate medially, forming a column of mesenchyme surrounding the notochord and the neural tube. Of all of the cells derived from one somite (a sclerotome unit), the cranial half of the unit is loosely arranged, while the caudal half is condensed. If you were to look at a histological section of the whole column, you would see an alternating pattern of densely packed and loosely packed cells. These two populations of cells have different characteristics. 1. Remember that the neural tube is just medial to the sclerotomes. Somehow, nerve fibers must penetrate this sclerotome column in order to follow their myotome or dermatome cells. Nerve fibers travel easily through the loose cranial sclerotome, while the dense caudal half inhibits nerve growth. a. The first motor axons exit the vertebral canal opposite the cranial half of a sclerotome unit. Later, other axons exit the spinal cord opposite the caudal half-sclerotome but are prohibited from passing through the dense caudal half and so enter the cranial half by joining the first neurons. As a result, we observe ventral and dorsal rootlets attached all along the spinal cord, but merging together at regular intervals to form individual spinal nerves. This subdivision of the sclerotome unit therefore imposes a segmental organization on the peripheral nervous system. b. Somites also play a role in the segmental pattern of dorsal root ganglia formation; neural crest cells that will give rise to the dorsal root ganglia also migrate into the cranial sclerotome, and thus dorsal root ganglia become segmented. Somites have additional varied and complex roles in neural crest cell migration. 4  2024 CHAPTER 16 c. Many factors, including extracellular matrix molecules and attractive and repulsive signaling molecules, mediate the preferential migration of axons and neural crest cells into the cranial portions of the somites. C. It might surprise you that each sclerotome unit does not make a single vertebra! The dense caudal half of one sclerotome fuses with the loose cranial half of the succeeding sclerotome to form one vertebra. This process is called “sclerotome resegmentation”. Therefore, the embryonic segments, the somites, and the adult segments, the vertebrae, are offset by a half-segment. However, the myotome retains its original segmentation (from the somite); in this way the musculature can bridge between vertebral bodies and allow movement across the intervertebral joints. 1. Intervertebral Disc - Although the notochord regresses entirely in the region of the vertebral bodies, it persists as the nucleus pulposus portion of the intervertebral discs. The nucleus pulposus is the soft center of the intervertebral disc. The remaining larger portion of the intervertebral disc, called the annulus fibrosus, consists of fibrocartilage that is derived from the cranial half of the sclerotome. D. Vertebral malformations 1. Block Vertebrae - two or more vertebrae fused together 2. Hemivertebrae - wedge-shaped IV. Muscular System A. The most recent evidence indicates that all skeletal muscle is derived from the myotome cells of somitomeres or somites, and then migrates into its proper position within the head, trunk or limbs. B. Myogenesis 1. After the somite has differentiated, the mesenchymal cells of the myotome split off, migrate to the proper site and become elongated, spindle-shaped myoblasts. Myoblasts, like most other "blasts", can undergo mitosis. At this point they are determined but not differentiated, and so are practically indistinguishable from other mesenchymal cells. 2. Several myoblasts fuse together to form long multinucleated myotubes which begin to produce the specialized proteins characteristic of differentiated muscle. a. Once myoblasts have fused, further division is impossible, though the immature syncytial muscle cell can enlarge by recruiting more myoblasts to fuse with it. 5 2024 CHAPTER 16 b. In the adult, a few myoblasts persist as small, flattened and inactive cells lying in close contact with the mature muscle fibers. When the muscle is damaged, these satellite cells can proliferate, and fuse to form new muscle fibers. They are the stem cells of skeletal muscle. C. The musculature of the body wall becomes divided into a small dorsal portion, the epimere, and a larger ventral part, the hypomere. 1. Epimere a. Epaxial Muscles - extensors of the vertebral column b. These muscles are innervated by dorsal branches of spinal nerves 2. Hypomere a. Hypaxial Muscles - lateral and ventral flexors of the trunk b. These muscles are innervated by ventral branches of spinal nerves 3. Due to the ribs, the intercostal muscles maintain their segmental character, as do the deep intrinsic back muscles (deeper than the ones you see in Gross). Elsewhere, myotome cells from several somites organize to form muscles that bridge several segments (i.e., external abdominal oblique). 4. Muscle from the somite migrates into the limbs and forms the limb musculature. 6