Cilia and Flagella: from Discovery to Disease Dylan J
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Dartmouth Undergraduate Journal of Science Volume 20 Article 2 Number 1 Assembly 2017 Cilia and Flagella: From Discovery to Disease Dylan J. Cahill Dylan Cahill, [email protected] Follow this and additional works at: https://digitalcommons.dartmouth.edu/dujs Part of the Engineering Commons, Life Sciences Commons, Medicine and Health Sciences Commons, Physical Sciences and Mathematics Commons, and the Social and Behavioral Sciences Commons Recommended Citation Cahill, Dylan J. (2017) "Cilia and Flagella: From Discovery to Disease," Dartmouth Undergraduate Journal of Science: Vol. 20 : No. 1 , Article 2. Available at: https://digitalcommons.dartmouth.edu/dujs/vol20/iss1/2 This Research Article is brought to you for free and open access by the Student-led Journals and Magazines at Dartmouth Digital Commons. It has been accepted for inclusion in Dartmouth Undergraduate Journal of Science by an authorized editor of Dartmouth Digital Commons. For more information, please contact [email protected]. BIOLOGY Cilia and Flagella: FromCilia and Discovery Flagella: to Disease From Discovery to Disease BY DYLAN CAHILL ‘18 Introduction certain insect sperm fagella (3, 5, 6). A unique Figure 1: Chlamydomonas intracellular transport mechanism known as reinhardtii, a single-celled, bi- In 1674, peering through the lens of a crude flagellate green alga, viewed intrafagellar transport is responsible for the light microscope, Antoni van Leeuwenhoek with a scanning electron assembly and maintenance of these organelles Chlamydomonas observed individual living cells for the frst time microscope. is (3, 6). Cilia and fagella are primarily composed a model organism in flagellar in history (1). He noted long, thin appendages of the protein tubulin, which polymerizes into dynamics and motility studies. protruding out of some of the otherwise globular long tracks called microtubules. However, cells that seemed to provide locomotion, like proteomic analysis, the analysis of the total “litle feet” (1, 2). Leeuwenhoek’s description of Source: Wikimedia Commons protein complement of a sample at a single time (Credit: Rippel Electron what we now know to be cilia, the frst organelle point, has revealed the presence of 600 – 1000 Microscope Facility, Dartmouth discovered, initiated centuries of research on the College) diferent polypeptides in a single fagellum (7, structure and function of this versatile organelle. 8). Cilia and fagella are hair-like organelles While many ciliary and fagellar proteins that project out from the cell surface in are known to play a structural role in the cilia eukaryotic organisms (3). Cilia come in two and fagella scafolding, known as the axoneme, varieties, motile cilia and non-motile, primary the structure and function of the majority of this cilia, and share many characteristics with diverse protein array remains unknown and is fagella. Te membranes of both cilia and an active area of research (4, 7). Recent research fagella are continuous with the cell membrane, has focused on the role cilia play in ciliopathies, but possess a distinctive lipid and protein a broad and enlarging class of diseases linked to composition (4). Most cilia and fagella are 200 defects in cilia, particularly primary cilia, as well – 300 nm in diameter and range from 1 – 5 μm as the role cilia may play in cancer progression. long for most cilia and up to more than 2 mm for FALL 2017 3 Cilia and Flagella: layer of cells; the mechanism by which cilia and The Dividing Line fagella generate propulsion also varies such that fagella primarily beat in a regular sine Cilia and fagella are so similar in terms wave motion while cilia move by a “power and of structure and function that the terms are recovery stroke” in much the same way that a ofen used interchangeably (4, 7). Structurally, swimmer’s arm generates thrust. Unlike fagella, cilia and fagella are identical; a cross section primary cilia are found on nearly all vertebrate of either organelle reveals the same ordered cells (8). arrangement of proteins in the axoneme, which is highly conserved across species (8). Te More than Movement following generalizations highlight their few distinguishing characteristics: cells typically A critical distinction within cilia is that have few, long fagella or many short cilia; between motile cilia and primary cilia, which fagella function to propel a cell through a liquid difer both structurally and functionally. medium whereas cilia, in addition to propelling Te structural component of motile cilia, some cell types through a liquid medium, the axoneme, has a “9+2” arrangement of function to propel fuid across a stationary microtubules in which 9 pairs of microtubule Figure 2: Primary cilium structure. a. Transmission electron microscopy of a primary cilium. b. Schematic of intraflagellar transport. c. Cross section of motile cilium with 9+2 microtubule arrangement and dynein arms. d. Cross section of primary cilium with 9+0 microtubule arrangement. Source: Waters, A. M., & Beales, P. L. (2011). Ciliopathies: An expanding disease spectrum. Pediatric Nephrology, 26(7), 1039-1056. doi: 10.1007/s00467-010-1731- 7. Reprinted with permission. 4 DARTMOUTH UNDERGRADUATE JOURNAL OF SCIENCE doublets surround a central pair of microtubule much of the material is applicable to motile cilia Figure 3: The four stages of singlets, as shown in Figure 2 (8). Motile cilia, also and fagella as well. primary cilia assembly. called secondary cilia, are capable of rhythmic movements that provide propulsion, such as Four-Stage Assembly Source: Pedersen, L. B., Veland, I. R., Schrøder J. M., in protists or spermatozoa, and function in the Primary cilia are assembled in four main passage of fuid over a stationary membrane, & Christensen, S. T. (2008). stages, according to the hypothesis illustrated Assembly of primary cilia. such as in the epithelia of the respiratory tract (6, in Figure 3 (10). In stage one, a membrane- Developmental Dynamics, 9). Underlying this motion are arms composed bound vesicle within the cell buds of the Golgi 237(8), 1993-2006. doi: of the motor protein dynein. Every motile cilium 10.1002/dvdy.21521. Reprinted apparatus, an organelle composed of layers of with permission. contains thousands of dynein proteins, each of membrane sacks that is involved in protein which is fxed in place on one end and free to packaging and modifcation. Tis vesicle merges walk a short distance along microtubule tracks with a centriole, a cylindrical organelle also at the other end. Tis structural arrangement of composed of microtubules, but in a triplet, not the axoneme gives cells the ability to coordinate a doublet, array, to form the centriolar vesicle. the walking of thousands of dynein proteins Te membrane-associated centriole, designated over short distances along the length of the as the “mother centriole,” forms the base of cilia. Te summation of this process generates the growing cilium (10). Te mother centriole “More recent bending and rhythmic beating (4, 8). begins to grow into the centriolar vesicle, which experimentation Primary cilia are non-motile organelles wraps around the centriole much like a partially found in most non-dividing vertebrate cells (2, and research defated balloon wraps around a fst pressed into has revealed that 8). Primary cilia lack dynein motor proteins and it. other structural features common to motile cilia, In stage two, the centriolar vesicle and primary cilia play such as the central pair of singlet microtubules, mother centriole migrate together toward the critical roles in and are therefore classifed as having a “9+0” cell membrane. Meanwhile, additional smaller arrangement of microtubules, also demonstrated diverse signaling vesicles called secondary centriolar vesicles pathways both in Figure 2. Because primary cilia are incapable fuse with the primary centriolar vesicle. Te of motion, some researchers initially concluded rudimentary axoneme growing out of the during development that primary cilia were merely vestigial mother centriole continues to grow rapidly and in maintaining structures (2). More recent experimentation through polymerization of tubulin at its tip. Te homeostasis.” and research has revealed that primary cilia extent to which cilium growth occurs during play critical roles in diverse signaling pathways transport before docking with the membrane both during development and in maintaining remains unknown (10). homeostasis (2). Primary cilia are optimized for In stage three, the centriolar vesicle fuses this signaling role via their unique, high-density with the cell membrane. Here, the nomenclature arrangement of receptors and ion channels changes and the mother centriole now becomes (2). Because of the growing interest in the link known as the basal body, the organelle at the between primary cilia and disease, the remainder base of the cilium (10). of this article focuses on primary cilia, although Finally, in stage four the primary cilium FALL 2017 5 is elongated and maintained by intrafagellar the microtubule-based axoneme in a particular transport, as discussed in the following section. direction. Microtubules have polarity inherent to their structure, which gives them a head or The Intraflagellar Transport Train “plus end” and tail or “minus end.” Kinesin-II and In the 1990s, advances in light microscopy OSM-3 are plus-end directed motor proteins that “IFT serves this transport proteins away from the cell body to function as a facilitated the discovery at Yale University of intrafagellar transport (IFT), a revolutionary the tip of the cilium in the anterograde direction bidirectional transport mechanism unique to cilia and fagella (7, 12). Cytoplasmic dynein (a version diferent transport system, (7, 11). Given that the proteins comprising the than the dynein atached to the outer doublets) moving protein axoneme of cilia and fagella are synthesized is a minus-end directed motor protein that transports proteins from the tip of the cilium to complexes from the in the cell body but assemble at the tip, the tip gets further away from the cell as the the cell body in the retrograde direction. Early base of the cilium fagellum grows.