Chapter 8 Nervous System Cont- Neural Crest PDF

Chapter 8 Chapter 8: Nervous System Continued: Neural Crest Key terms and concepts: Neural crest cell Cell migration Epithelial-mesenchymal transition (EMT) (review) Cell adhesion Schwann cell Peripheral nerve/peripheral nervous system Melanocyte cKit (Kit) gene Autonomic ganglia Enteric...

Chapter 8 Chapter 8: Nervous System Continued: Neural Crest Key terms and concepts: Neural crest cell Cell migration Epithelial-mesenchymal transition (EMT) (review) Cell adhesion Schwann cell Peripheral nerve/peripheral nervous system Melanocyte cKit (Kit) gene Autonomic ganglia Enteric nervous system Aganglionosis Overo lethal white syndrome Endothelin receptor B, Myelinated, myelin Learning objectives: By the end of this unit, you should be able to: 1. Explain how neural crest cells form and their germ layer of origin. 2. What role(s) do cell migration and cell adhesiveness play in neural crest cell development? 3. Explain the role of the process of epithelial to mesenchymal transition (EMT) in neural crest cell biology. 4. Name at least five tissues that derive from the neural crest. 5. Explain one broad difference between the central nervous system and the peripheral nervous system. 6. Explain the origin of the enteric nervous system and describe the effect of congenital defects in it. 7. Name the cells responsible for myelination in the peripheral nervous system and in the central nervous system. What role does myelination play in development? 8. Explain the embryonic basis for the spectrum of abnormalities seen in equine Overo lethal white syndrome. 9. Outline how Endothelin receptor B influences neural crest development in broad terms. Explain the impact of mutation of this receptor on neural crest cells in horses. 1  Chapter 8 I. Formation of the Neural Crest CONCEPT: Migratory Cells It's not unusual for embryonic cells to wander around a bit within their proper territory. However, there are some cells that don't just wander locally, but undertake long migrations from their site of origin, where they first become determined, to colonize distant parts where further cell differentiation will take place. Movement of these cells is fairly precise and ceases once they have reached their target. Many guidance cues in the embryo, importantly including extracellular matrix elements, guide neural crest cell migrations. A. Neural crest cells develop from the neuroectoderm at the edges of the neural folds delaminate (detach) from the neural tube, undergo an epithelial to mesenchymal transition (EMT), and migrate to form a wide range of structures. Signaling from the surface ectoderm, mediated by BMP factors, is important in neural crest specification. B. The neural crest cells are migratory, and migrate extensively through the embryo to contribute to a wide range of structures. Like many other tissues, they appear in a cranial-to-caudal wave along the neural axis. C. The EMT is accompanied by changes in cell adhesiveness due at least in part to changes in cell adhesion molecule expression. Concept: Epithelial-Mesenchymal transition (EMT)- The so-called “epithelial- mesenchymal transition” (EMT) is a very important cellular process that occurs in embryos (and in cancer). Through the process of EMT, orderly, precisely arranged epithelial cells transition to a migratory mesenchymal cell phenotype. As you learned in chapter 5, this process plays a key role in gastrulation. EMT is also crucial in the development of neural crest cells; neural crest cells originate as cells of the neuroectoderm and transition to a migratory cell type that will contribute to many cells of the body. In some instances, the neural crest cells will transition back to an epithelial morphology when they reach their destination (a Mesenchymal to Epithelial transition or MET). The EMT involves changes of expression of many different genes important in a variety of cell processes. For example, regulation of genes involved in cell adhesion (such as cadherin proteins) and cell-cell junction formation is important in modulating the EMT. Transcription factor expression by neural crest cells undergoing EMT drive many of these key changes in gene expression. 2  Chapter 8 Wow! EMT is important in disease too!- EMT is also a critically important mechanism in cancer. Neoplastic (cancerous) epithelial cells can sometimes undergo EMT and invade into tissues surrounding the tumor and beyond. If you are interested in learning more about this mechanism that links development and cancer, several recent review papers have been published including: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182759/ D. Neural crest cells give rise to a dazzling array of neural and non-neural cell types and may migrate deep into the embryo to form them. In addition to the specific types of neurons and glial cells described below, neural crest derivatives also include: 1. Connective tissues of the head (including bone, cartilage, dermis, and other elements). 2. Cells within the outflow region (spiral septum) of the heart. 3. Pigment cells (melanocytes) in the skin. 4. The adrenal medulla (adrenal chromaffin cells), carotid body, parafollicular cells(C- cells) of the thyroid, and some other neuro- secretory cells. 5. Neurons and glia of the peripheral nervous system including both sensory and autonomic divisions (see below). 6. Elements of the inner ear. Seeing spots: cKit and Kit ligand in the neural crest: cKit is a cell surface receptor of the membrane receptor tyrosine kinase family. cKit is expressed by neural crest cells as well as a variety of other cell types and structures in the developing embryo. Binding of the extracellular portion of cKit by its ligand, termed Kit ligand (aka stem cell factor or Steel factor) triggers a cascade of signal transduction that mediates a wide range of functions including cell survival, proliferation, and migration depending on cell type. cKit signaling plays important roles in development of neural crest cells, notably in melanocyte precursors. Mutations in the Kit gene have been identified in several white spotting and white coat color phenotypes in a variety of Veterinary species such as pigs, horses, mice, cattle, and even cats. E. Neural crest fate specification is a complex process that is incompletely understood. Neural crest cells are influenced extensively by the signals the cells receive during migration and can exhibit plasticity in their cell fate. However, there is also evidence that neural crest cells are patterned prior to migration. 1. Components of the extracellular matrix through which neural crest cells migrate are often important in guiding their migration. 2. Extrinsic signals to neural crest cells from their environment can modulate their identity and behavior. 3. Intrinsic properties of the cells can also play a role in their development. 3  Chapter 8 F. Among the cells formed from neural crest are most neurons whose cell bodies lie outside the central nervous system (therefore in ganglia). [Remember that neurons whose cell bodies lie within the CNS are formed from the neural tube.] Nervous system cells derived from neural crest include: 1. Sensory neurons within spinal (sensory, dorsal root) ganglia 2. Neurons within autonomic ganglia. These are the cell bodies of the second neurons in the sympathetic or parasympathetic pathways (postganglionic neurons). Examples of autonomic ganglia are those found along the sympathetic trunk, and those found within the walls of organs (intramural). 3. The neurons of the enteric nervous system; The enteric nervous system is a subdivision of the autonomic nervous system. It comprises the nerves in the walls of the intestines that control peristalsis among other elements of gut function. Neural crest cells from the vagal (cervical) and sacral regions of neural crest contribute to the enteric nervous system. a. Aganglionic large intestines- What purpose do the autonomic fibers to the intestine serve? What would happen if they were missing? What abnormal situation(s) might cause them to be missing? Overo Lethal White Syndrome (OLWS) – OLWS occurs in newborn foals that inheret a copy of the mutated OLW gene from each parent. Horses with white Overo patterning are more likely carriers of the gene than solid-colored horses. The Overo coat pattern is described as white markings on the lateral and ventral aspects of the neck and torso. The mutated gene, endothelin receptor B (Ednrb), alters neural crest cell formation of melanocytes and intestinal ganglia. Affected foals suffer from aganglionosis of the intestinal intramural ganglia, resulting in intestinal immotility and death within a few days after birth. The altered gene also causes lack of skin pigmentation and white coat color. For information regarding Overo lethal white foal syndrome from the University of Minnesota extension see: https://extension.umn.edu/horse-health/overo-lethal-white-syndrome-olws 4  Chapter 8 Endothelin receptor B (EDNRB)- The gene responsible for Overo lethal white foal syndrome is the Ednrb gene. EDNRB is a G-protein coupled cell membrane receptor expressed by various neural crest cells including those destined to form both melanocytes and the enteric nervous system. In the developing GI tract, Ednrb is expressed by neural crest cells destined to form the enteric nervous system as well as some other non-neural crest cells. The ligand for EDNRB, endothelin-3 (EDN-3) is expressed by the gut mesenchyme in mice. Activation of EDNRB on neural crest cells by binding of its EDN ligand in the GI mesenchyme modulates the ability of neural crest cells to colonize the GI tract. Mutations in Ednrb disrupt this process. EDN-3/EDNRB signaling also has several roles in melanocyte development, and animals with EDN-3 or EDNRB mutations often exhibit pigmentation changes. In mice, migration and/or survival of melanocyte precursor cells seems to be the most likely mechanism of the pigment defects in Ednrb mutants. 4. Schwann cells - These are supportive cells that surround and insulate the long processes of neurons traveling through the PNS (they perform the same function in the PNS that oligodendrocytes perform in the CNS. Recall that oligodendrocytes are neuroectodermal in origin). Many axons are "myelinated" by Schwann cells (PNS) or oligodendrocytes (CNS). These cells wrap concentric layers of their own lipid-containing plasma membrane around the axon to act as an insulator (just as a copper wire is covered by plastic). By reducing the leakage of electrical current from the axon membrane, myelin allows signals (action potentials) to travel faster and more efficiently. a. Many axons are not myelinated until after birth. This is one reason that many animals have poor motor abilities as newborns. In general, increased function reflects myelination. Would you expect that all species are at the same stage of myelination at birth? What other factors affect the ability to stand and walk at birth? b. Abnormal myelination - Congenital myelin defects, or diseases which later in life destroy myelin, often result in uncontrollable tremors, or paralysis and weakness. 5. Inner ear- Melanocytes and possibly other neural crest cells contribute to formation of the inner ear. There are associates between some pigment defects and deafness in various species including dogs, cats, and horses. Thought questions: What do your brain and skin have in common, embryologically speaking, and what event made them different? Postulate some developmental defects which might occur as a result of errors in neural crest migration. 5