Chapter 6 CNS PDF

Chapter 6 Chapter 6: Intro to Organogenesis- Nervous System, Neurulation and the Neural Tube Key terms and concepts: Neurulation Encephalocele Central nervous system Exencephaly Notochord Brain ventr...

Chapter 6 Chapter 6: Intro to Organogenesis- Nervous System, Neurulation and the Neural Tube Key terms and concepts: Neurulation Encephalocele Central nervous system Exencephaly Notochord Brain ventricles Ectoderm Hydrocephalus Neuroectoderm Holoprosencephaly Induction Sonic hedgehog (Shh) Neural plate Bone morphogenetic protein (BMP) Neural folds N-cadherin, E-cadherin Neural tube Prosencephalon Neural tube closure/fusion Mesencephalon Spina bifida Rhombencephalon Learning objectives: By the end of this unit, you should be able to: 1. Explain in simple terms what is meant by the central nervous system. 2. Identify the embryonic structure that forms the central nervous system and name the germ layer of origin of that structure. 3. Describe the “potency” of neuroectodermal cells. 4. Explain the process of induction and name examples of induction that occur during nervous system development. What developmental structures are involved? 5. Name the early subdivisions of the developing brain and know what brain regions (roughly) they will form in the adult animal. 6. Explain the importance of neuropore closure during neural development. 7. Understand the embryologic basis for the several developmental defects of the central nervous system discussed in the notes and in class. 8. Understand what is meant by “pattern formation” in the central nervous system. 9. Name at least two molecules involved in patterning the nervous system and explain what they do. I. Introduction A. Once gastrulation has occurred, and the three germ layers of the embryonic disc are in place, several organ-forming processes begin simultaneously. The nervous system is among the first to begin development, and one of the last to complete maturation. The early development of the nervous system, including the induction of the neural plate (the thickened midline strip of ectodermal cells destined to become the central nervous system- called the neruoectoderm) and neural tube closure is called neurulation. 1  Chapter 6 What have you observed about newborn animals that demonstrates that the nervous system is immature at the time of birth? Would you expect that the nervous systems of species differ in their degree of maturity at the time of birth? Compare the ability of a calf, a puppy and a baby to walk at birth. B. If we were to look down from above on the surface of the embryonic disc, we would see the outermost germ layer, ectoderm. Immediately underneath this is mesoderm. Remember that the notochord is a special mid-line rod-shaped condensation of mesoderm which was formed during gastrulation. 1. The notochord, and prechordal plate in the head region, in an as yet unknown way, causes the overlying ectodermal cells to become irreversibly destined to become neural tissue. As part of its response, the ectodermal layer becomes thickened over the notochord, forming the neural plate. CONCEPT: Induction Many tissues develop as a result of interactions between two or more groups of cells with separate origins which are brought into contact. The process by which the differentiation of one tissue is controlled by a second tissue in close contact with it is induction. Induction requires a tissue capable of producing a stimulus (often a chemical) and a tissue capable of responding to it. No tissue is able to form an organ by itself; it must interact with other tissues, usually through induction. 2  Chapter 6 2. As the ectoderm thickens over the notochord, the lateral edges of the neural plate become increasingly elevated to form a neural groove bounded on either side by raised neural folds. Eventually the folds meet and fuse to form the hollow neural tube, roofed over by a continuous sheet of ectoderm (which will become skin). The fusion of the tube begins in what will become the cervical area and proceeds rostrally and caudally. Thus, closure takes time and does not occur simultaneously along the whole neural tube. The rostral and caudal ends of this tube remain temporarily open at the neuropores. Defects in neural tube closure can result in developmental anomalies, specifically spina bifida, encephalocele, exencephaly or anencephaly. a. Encephalocele – Incomplete closure of the cranial neuropore. Because the edges of the neuropore don’t fuse with each other, the skull can't form around the brain, causing protrusion of the brain and membranes. b. Exencephaly – Complete failure of the cephalic (cranial) neural tube to close. The brain that remains in contact with the amniotic fluid degenerates, producing a condition called anencephaly, or an absence of the brain. Anencephaly is very severe and all of those affected die shortly after birth. c. Spina bifida - defective or absent vertebral arch, often with some degree of spinal cord abnormality; most cases of spina bifida result from failure of the neural groove (most often the caudal end) to close, which makes it impossible for the vertebral arch to complete its dorsal growth around the spinal cord. The severity can vary greatly, from cosmetic to debilitating. 3. The expression of distinct cell adhesion molecules (cadherins) by the neural tube is important in mediating the eventual separation of the neuroectoderm (which expresses N-cadherin) from the surface ectoderm (which expresses E-cadherin). The differences in cell adhesion molecule expression prevent these two ectodermal derivatives from sticking to each other. 4. Complex patterns of gene expression of transcription factor genes, importantly of the Hox gene families, are induced along the cranial/caudal axis of the developing neural tube. It is these patterns of gene expression that specify/determine the spatial identity (pattern formation) of the neural tube along its cranial/caudal axis. 3  Chapter 6 a. The pattern of Hox gene expression is sensitive to Retinoic Acid exposure. Normally, there is a gradient of retinoic acid in the embryo, higher in caudal regions than in cranial. The retinoic acid gradient is established by caudal expression of retinoic acid synthesizing enzymes and cranial expression of retinoic acid degrading enzymes. Exposure of embryos to excessive exogenous retinoic acid can perturb Hox gene expression. 5. Patterns of differential gene expression are also induced in dorsal and ventral domains of the developing neural tube, and these are involved in specifying the dorsal and ventral identities (pattern formation) of the regions in which they are expressed. a. Sonic Hedgehog (Shh) protein is a growth factor. Shh from the notochord signals ventral identity to the overlying neuroectoderm. Shh from the notochord signals the medial ventral neural tube cells to become the floor-plate. The floor plate, in turn, secretes Shh which forms a gradient across the neural tube that is highest in ventral regions and is key in patterning the ventral identity of the neural tube. b. Tgf-beta family proteins are also growth factors. Tgf-beta family proteins such as various bone morphogenetic proteins (BMP’s), which originate from the overlying ectoderm, signal dorsal identity to the underlying neural tube. c. The patterning signals received by different regions of the developing neural tube specify different cell identities. In this way, cells within the various regions go on to form appropriate cell types. For example, motor neurons arise in the ventrolateral spinal cord and are specified by appropriate levels of Shh and TGF-beta family proteins. By combining cranial/caudal and dorsal/ventral patterning information, cells can be uniquely specified for their anatomic location. 6. The central nervous system is defined as the brain and spinal cord. The peripheral nervous system is defined as the nervous tissue beyond the CNS, such as the spinal nerves. Some individual neurons, such as interneurons, lie completely in the CNS. Others, such as many motor neurons, are partly in the CNS, partly in the PNS. Although it is a bit of a simplification that we can be more specific about later, we can say that the central nervous system (the brain and spinal cord) will develop from the neural tube. II. Histogenesis In The Developing Neural Tube A. Histogenesis is the formation of different tissues from undifferentiated cells. B. The early neural tube is composed of primitive neuroectodermal cells, which comprise a pseudostratified columnar layer of cells. 4  Chapter 6 C. The neuroectodermal cells are MULTIPOTENT and will give rise to four different cell types in the adult: 1. Neurons 2. Macroglia (2 types) a. Astrocytes b. Oligodendrocytes- these are the myelinating cells of the CNS 3. Ependyma- these are the cells that line the ventricular system in the adult D. The primitive neuroectodermal cells proliferate in the cell layer surrounding the central canal/ventricular system of the developing neural tube. This germinal layer (germinal zone) becomes known of as the ventricular zone. Eventually the ventricular zone divides to form the ventricular and subventricular zones, both of which will give rise to the precursor cells that will form the CNS. Note that in recent years it has been discovered that neural stem cells remain active even in adult animals in regions of the sub-ventricular zone, as well as in a few other specialized areas of the brain, such as parts of the hippocampus, in a variety of species. III. Early Brain Development A. Early on, the rostral end of the neural tube expands very rapidly to form the brain. This dramatic enlargement occurs primarily as a result of an increase in the size of the lumen, rather than by tissue growth in the tube wall. The primary mechanism involved appears to be fluid pressure. At the junction between the brain and spinal cord, the neural canal (=spinal canal) temporarily becomes constricted, forcing the buildup of pressure within the rostral neural tube from the CSF fluid produced there. After this initial rapid enlargement of the brain, the narrowed region of the neural canal reopens, releasing the pressure. B. From an original three dilations, five major subdivisions of the brain develop. The general organizational plan seen in the spinal cord (alar vs. basal) is also followed in the brain, with variations due primarily to different amounts of growth of some parts relative to others and migration of cell bodies. 5  Chapter 6 1. Telencephalon - cerebral hemispheres (thinking, personality) 2. Diencephalon - thalamus (sensory and motor relay and integration) 3. Mesencephalon - midbrain (auditory and visual reflexes) 4. Metencephalon - cerebellum and pons (motor coordination) 5. Myelencephalon - medulla oblongata (origin of several cranial nerves) Holoprosencephaly – Normally, the rostral forebrain splits into two cerebral hemispheres; failure to form these two hemispheres results in holoprosencepahly, a condition associated with cyclopia. Pregnant animals that eat a certain plant at a specific stage in gestation will give birth to young with holoprosencephaly/cyclopia. We now know that a particular compound in plant, named cyclopamine, is a specific inhibitor of the Sonic Hedgehog pathway and is responsible for these birth defects. The sensitivity of the embryo to cyclopamine during certain times is an example of the importance of Critical Periods. 6. Cerebellar hypoplasia - What does "hypoplasia" mean? It means under or incomplete development. Considering what the cerebellum does, what would the symptoms of cerebellar hypoplasia be? How might an embryo or fetus be exposed to the following viruses, which can cause this defect? a. Feline panleukopenia virus and bovine virus diarrhea virus are known to cause cerebellar hypoplasia. C. Ventricles 1. The original lumen of the hollow neural tube expands greatly in some areas of the developing brain, forming the ventricular system, which is continuous with the central canal of the spinal cord and with the subarachnoid space of the meninges. These spaces are lined by ependymal cells. 2. A special tissue within some of these spaces, the choroid plexus, produces cerebrospinal fluid (CSF), which circulates through the ventricles. It is normally reabsorbed into the venous system at the same rate at which it is produced, so there is constant renewal of it. a. Hydrocephalus - Buildup of CSF in the ventricles due to an imbalance between production and reabsorption of CSF. This can be congenital or acquired. Would this condition affect an adult differently than an infant? 6