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Chapter 8 : Cell Cycle and Growth Control in Candida Species
Category: Fungi and Fungal Pathogenesis; Clinical Microbiology
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This chapter describes the major Candida albicans morphologies and the current understanding of the cell biological and cell cycle features that distinguish them. It highlights recent insights into how cell cycle regulators influence the formation of hypha-specific cellular features in particular. Since morphogenesis and cell cycle regulation have been studied most extensively in C. albicans, the chapter primarily focuses on work in C. albicans. The important distinction between yeast and pseudohyphae is that pseudohyphae spend more time in G2 phase of the cell cycle than yeast cells , and they continue to elongate during this time. There has long been a controversy as to how pseudohyphae are related to true hyphae. Initial models suggested that yeast cells, pseudohyphae, and true hyphae reside along a continuum. Later, based on differences in cell cycle dynamics and subcellular structures, it was proposed that pseudohyphae and hyphae represent two distinct morphological states, with pseudohyphae being more like yeast form growth with respect to cell cycle progression and cell biological markers. Recent work has shed light on cell biological features associated with cell cycle progression in chlamydospores and is discussed in theis chapter. In the C. albicans genome sequence, there are three G1 cyclins (Ccn1, Cln3, and Hgc1) and two G2 or B-type/mitotic cyclins (Clb2 and Clb4) that are predicted to associate with Cdc28.
Different C. albicans morphologies imaged by differential interference contrast microscopy: (a) yeast cells; (b) true hyphae (arrow, septum); (c) pseudohyphae; (d) chlamydospore (arrow) on a suspensor cell (arrowhead); (e) opaque cells. Scale bars, 10 µm. doi:10.1128/9781555817176.ch8.f1
Dynamics of organelles and cytoskeletal components during cell cycle progression in yeast and the first cell cycle of pseudohyphae and hyphae following induction of unbudded yeast cells. Hyphal germ tubes emerge prior to the G1/S transition. The localization patterns of cytoskeletal elements are described in more detail in the text. Reprinted from reference 124 with permission from Elsevier. doi:10.1128/9781555817176.ch8.f2
Method of calculation of the Mi ( 87 ). l, length; d, maximum diameter; s, diameter at mother-daughter cell junction. The morphology ratio (l/d) has a value near 1.0 in a sphere and becomes larger in a more filamentous cell. doi:10.1128/9781555817176.ch8.f3
Spitzenkörper (a and b) and polarisome (d) structures at C. albicans hyphal tips. FM4-64-stained vesicles (a, asterisk) and Mlc1-YFP (b) localize apically to a spherical body. Polarisome-associated protein Bud6 tagged with YFP localizes in a crescent at hyphal tips (d; corresponding differential interference contrast image is in panel c). Scale bars, 2 µm (a), 10 µm (b), and 1 µm (c). Inset (b, square), magnification of ×5. doi:10.1128/9781555817176.ch8.f4
Relationship between vacuolar inheritance and hyphal elongation during cell cycle progression. Cell cycle progression is noted by the arrow to the left. Prior to mitosis, the parental vacuole enlarges relative to the total cell volume. Sub-apical hyphal cells contain large vacuoles and pause at G1 phase; apical cells have smaller vacuolar volumes (and thus a higher volume of cytoplasm) and actively progress through the cell cycle. Prior to branching (reentry into the cell cycle [bottom panel]), subapical cell vacuoles become smaller and the volume of cytoplasm becomes larger relative to the total cell volume. Gray, vacuole; black, nucleus; black line, septum; gray line, septin ring (“presumptum”). Adapted from references 124 and 13 with permission from Elsevier and the American Society for Microbiology. doi:10.1128/9781555817176.ch8.f5
Septin localization during the C. albicans cell cycle. Shown are time-lapse differential interference contrast (top panel of each set) and fluorescence (bottom panel of each set) images of C. albicans cells expressing a Cdc10 septin-yellow fluorescent protein fusion protein. In pseudohyphae (A), a septin cap localizes to the presumptive pseudohyphal bud site in G1 phase (a). Throughout the S and G2 phases, the septins organize into a collar at the mother-bud neck (b). At mitosis, the septin collar splits into two rings (c). Cytokinesis occurs between the two rings, the rings disassemble, and the new septin cap appears during the next G1 (d and e). Bar, 5 µm. In hyphae (B), as the germ tube emerges, a septin spot localizes to the hyphal tip (a, asterisk) and a basal septin band is visible at the mother-daughter neck (a, arrow). The classic septin ring marks the future site of septation (the presumptum; b, arrow). At later time points, the septin ring splits into two rings (c, arrowhead). Bar, 10 µm. doi:10.1128/9781555817176.ch8.f6
Cell cycle progression and cyclin levels differ in yeast cells and hyphae. In general, G1 cyclins persist longer and mitotic cyclins appear later in hyphae than in yeast cells. Adapted from data in references 20 , 22 , 79 , and 136 . doi:10.1128/9781555817176.ch8.f7
Model of G1 cyclin-mediated maintenance of C. albicans hyphal growth and hyphaspecific cellular features. Two cyclin-CDK complexes, Ccn1-Cdc28 and Hgc1-Cdc28, act sequentially to activate the Cdc11 septin and to promote polarized growth. In addition, Hgc1-Cdc28 phosphorylates, and inhibits the localization of, the Cdc42 GAP Rga2, which results in enhancement of Cdc42 activity at the hyphal tip. Hgc1-Cdc28 also promotes the maintenance of cell-cell attachments through two pathways: phosphorylation of Sep7 to prevent Cdc14 from acting at the septum and phosphorylation of Efg1 to inhibit the expression of Ace2-activated target genes. HGC1 expression is partially dependent upon the hypha-specific transcriptional activator UME6 ( 28 , 144 ). Dotted arrows with question marks indicate possible interactions that have not been demonstrated conclusively. doi:10.1128/9781555817176.ch8.f8
Cell biological features of Candida albicans morphologies a
Cell cycle-related gene sequences in C. albicans