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Stephane Sarrazin William C. Lamanna Jeffrey D. Esko 《Cold Spring Harbor perspectives in biology》2011,3(7)
Heparan sulfate proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions. Here, we discuss changing views on the specificity of protein–heparan sulfate binding and the activity of HSPGs as receptors and coreceptors. Although few in number, heparan sulfate proteoglycans have profound effects at the cellular, tissue, and organismal level.Heparan sulfate proteoglycans (HSPGs) are glycoproteins, with the common characteristic of containing one or more covalently attached heparan sulfate (HS) chains, a type of glycosaminoglycan (GAG) (Esko et al. 2009). Cells elaborate a relatively small set of HSPGs (∼17) that fall into three groups according to their location: membrane HSPGs, such as syndecans and glycosylphosphatidylinositol-anchored proteoglycans (glypicans), the secreted extracellular matrix HSPGs (agrin, perlecan, type XVIII collagen), and the secretory vesicle proteoglycan, serglycin (Esko et al. 1985), which allowed functional studies in the context of a cell culture model (Zhang et al. 2006). A decade later, the first HSPG mutants in a model organism (Drosophila melanogaster) were identified (Rogalski et al. 1993; Nakato et al. 1995; Häcker et al. 1997; Bellaiche et al. 1998; Lin et al. 1999), which was followed by identification of mutants in nematodes, tree frogs, zebrafish, and mice (and3).3). HS is evolutionarily ancient and its composition has remained relatively constant from Hydra to humans (Yamada et al. 2007; Lawrence et al. 2008).
Open in a separate windowHS, heparan sulfate; CS, chondroitin sulfate; PG, proteoglycan.aThe variation in core mass is because of species differences.bThe number of chains is based on the number of putative attachment sites for chain initiation as well as data from the literature; the actual number of chains varies by method, tissue, and species.
Open in a separate window
Open in a separate windowFigure 1 shows in pictorial form many of the systems in which HSPGs participate.
Table 1.
Heparan sulfate proteoglycansClass | Proteoglycan | Core mass (kDa)a | Chain type (number)b | Tissue | Human disease |
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Membrane-bound | Syndecan-1–syndecan-4 | 31–45 | HS (2–3) in Sdc2 and Sdc4; HS/CS (3–4 HS/1-2 CS) in Sdc1 and Sdc3 | Epithelial cells, fibroblasts | |
Glypican-1–glypican-6 | 57–69 | HS (1–3) | Epithelial cells, fibroblasts | Simpson–Golabi–Behmel syndrome (overgrowth) (GPC3) (Pilia et al. 1996); omodysplasia (skeletal dysplasia) (GPC6) (Campos-Xavier et al. 2009) | |
Betaglycan (part-time PG) | 110 | HS/CS (1–2) | Fibroblasts | ||
Neuropilin-1 (part-time PG) | 130 | HS or CS (1) | Endothelial cells | ||
CD44v3 | 37 | HS (1) | Lymphocytes | ||
Secretory vesicles | Serglycin | 10–19 | Heparin/CS (10–15) | Mast cells, hematopoietic cells | |
Extracellular matrix | Perlecan | 400 | HS (1–4) | Basement membranes | Schwartz–Jampel syndrome (skeletal dysplasia) (Nicole 2000; Arikawa-Hirasawa et al. 2001) |
Agrin | 212 | HS (2–3) | Basement membranes | ||
Collagen XVIII | 150 | HS (1–3) | Epithelial cells, basement membranes | Knobloch syndrome type I (Sertie et al. 2000) |
Table 2.
Mutants altered in HSPG core proteinsGene | Proteoglycan | Phenotype (references) |
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Sdc1 | Syndecan-1 | Null allele: viable; increase in inflammation-mediated corneal angiogenesis (Gotte et al. 2002, 2005); corneal epithelial cells migrate more slowly, show reduced localization of α9 integrin during wound closure and fail to increase in proliferation after wounding (Stepp et al. 2002); enhanced leukocyte-endothelial interaction in the retina (Gotte et al. 2002, 2005); increase in medial and intimal smooth muscle cell replication and neointimal lesion after injury (Fukai et al. 2009); reduced cardiac fibrosis and dysfunction during angiotensin II–induced hypertension (Schellings et al. 2010); not required for follicle initiation and development (Richardson et al. 2009); accumulates plasma triglycerides, and shows prolonged circulation of injected human VLDL and intestinally derived chylomicrons (Stanford et al. 2009); juvenile mice resistant to carcinogen-induced tumorigenesis (McDermott et al. 2007); increased basal protein leakage and more susceptible to protein loss induced by combinations of IFN-γ, TNF-α, and increased venous pressure (Bode et al. 2008); exacerbates anti-GBM nephritis shifting Th1/Th2 balance toward a Th2 response (Rops et al. 2007); no role in hepatocyte infection by Plasmodium yoelii sporozoites (Bhanot 2002); normal larval development of Trichinella spiralis, but modestly reduced Th2 responses during infection (Beiting et al. 2006); less susceptible to Pseudomonas aeruginosa infection (Haynes et al. 2005); reduced P. aeruginosa infection rate and virulence (Park et al. 2001); protected from Staphylococcus aureus beta-toxin-induced lung injury (Hayashida et al. 2009a); exaggerated airway hyperresponsiveness, eosinophilia, and lung IL-4 responses to allergens (Xu et al. 2005); exaggerated CXC chemokines, neutrophilic inflammation, organ damage, and lethality in LPS endotoxemia (Hayashida et al. 2009b); prolonged recruitment of inflammatory cells in dextran sodium sulfate (DSS)-induced colitis and delayed type hypersensitivity (Masouleh et al. 2009; Floer et al. 2010). |
Sdc2 | Syndecan-2 | No mutants reported. Sdc2 antisense impairs angiogenesis in human microvascular endothelial cells (Noguer et al. 2009); morpholinos inhibit cell migration and fibrillogenesis during embryogenesis in zebrafish (Arrington and Yost 2009). |
Sdc3 | Syndecan-3 | Null allele: viable; altered feeding behavior (Strader et al. 2004); no phenotype in synovial endothelial cells (Patterson et al. 2005); enhanced long-term potentiation (LTP) in area CA1 (brain) and impaired performance in tasks assessing hippocampal function (Kaksonen et al. 2002); more sensitive to inhibition of food intake by the melanocortin agonist MTII (Reizes et al. 2003); perturbs laminar structure of the cerebral cortex as a result of impaired radial migration, and neural migration in the rostral migratory stream is impaired (Hienola et al. 2006); novel form of muscular dystrophy characterized by impaired locomotion, fibrosis, and hyperplasia of myonuclei and satellite cells (Cornelison et al. 2004). |
Sdc4 | Syndecan-4 | Null allele: viable; enhanced fibrin deposition in degenerating fetal vessels in the placental labyrinth (Ishiguro et al. 2000); delayed angiogenesis in wound granulation tissue (Echtermeyer et al. 2001); defective subcellular localization of mTOR Complex2 and Akt activation in endothelial cells, affecting endothelial cell size, NOS, and arterial blood pressure (Partovian et al. 2008); decreased macrophage uptake of phospholipase A2-modified LDL (Boyanovsky et al. 2009); mesangial expansion, enhanced matrix collagens I and IV, fibronectin and focal segmental glomerulosclerosis in males, and induction of Sdc2 in glomeruli (Cevikbas et al. 2008); more susceptible to hepatic injury, and thrombin-cleaved form of osteopontin is significantly elevated after concanavalin-A injection (Kon et al. 2008); less damage in osteoarthritic cartilage in a surgically induced model of osteoarthritis (Echtermeyer et al. 2009); explanted satellite cells fail to reconstitute damaged muscle and are deficient in activation, proliferation, MyoD expression, myotube fusion, and differentiation (Cornelison et al. 2004); vibrissae are shorter and have a smaller diameter because of suboptimal response to fibroblast growth factors (Iwabuchi and Goetinck 2006); lower phosphorylation levels of focal adhesion kinase (Wilcox-Adelman et al. 2002); random migration of fibroblasts as a result of high delocalized Rac1 activity (Bass et al. 2007); defective RGD-independent cell attachment to transglutaminase-fibronectin matrices (Telci et al. 2008); impaired suppression of production of IL-1β by TGF-α (Ishiguro et al. 2002); decreased neutrophil recruitment and increased myofibroblast recruitment and interstitial fibrosis after bleomycin-treatment, no inhibition of fibrosis with recombinant CXCL10 protein (Jiang et al. 2010); hypersensitivity to LPS because of decreased TGF-β suppression of IL-1 production in monocytes and neutrophils (Ishiguro et al. 2001). |
Gpc1 | Glypican-1 | Null allele: viable; reduced brain size (Jen et al. 2009). Athymic mutant mice show decreased tumor angiogenesis and metastasis (Aikawa et al. 2008). |
Gpc2 | Glypican-2 | No mutants reported. |
Gpc3 | Glypican-3 | Null allele: viable; resembles Simpson–Golabi–Behmel overgrowth syndrome, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly (Cano-Gauci et al. 1999; Chiao et al. 2002); defects in cardiac and coronary vascular development (Ng et al. 2009); alterations in Wnt signaling, in vivo inhibition of the noncanonical Wnt/JNK signaling, activation of canonical Wnt/β-catenin signaling (Song et al. 2005); increased Hedgehog signaling (Capurro et al. 2008); abnormal rates of proliferation and apoptosis in cortical and medullary collecting duct cells (Grisaru et al. 2001); delay in endochondral ossification, impairment in the development of the myelomonocytic lineage (Viviano et al. 2005). |
Gpc4 | Glypican-4 | Zebrafish knypek controls cell polarity during convergent extension (Topczewski et al. 2001); craniofacial skeletal defects in adult fish (LeClair et al. 2009). |
Gpc5 | Glypican-5 | No mutants reported. |
Gpc6 | Glypican-6 | Impaired endochondral ossification and omodysplasia (Campos-Xavier et al. 2009). |
Tgfbr3 | Betaglycan | Null allele: embryonic lethal; heart and liver defects (Stenvers et al. 2003); defect in seminiferous cord formation in E12.5–13.5 embryos (Sarraj et al. 2010). |
Hspg2 | Perlecan | Null allele: embryonic lethal (E10–12); developmental angiogenesis altered in zebrafish (Zoeller et al. 2009); high incidence of malformations of the cardiac outflow tract, lack of well-defined spiral endocardial ridges (Costell et al. 2002); lower amounts of collagen IV and laminins in embryonic hearts, reduced function in infarcted hearts from heterozygous mice (Sasse et al. 2008); absence of acetylcholinesterase at the neuromuscular junctions (Arikawa-Hirasawa et al. 2002); cephalic and skeletal abnormalities (Arikawa-Hirasawa et al. 1999); cerebral ectopias, exencephaly (Girós et al. 2007); increased cross-sectional area of myosin heavy chain type IIb fibers in the tibialis anterior muscle (Xu et al. 2010b); diminished osteocyte canalicular pericellular area (Thompson et al. 2011). |
Exon 3 deletion (Hspg23/3) viable: proteinuria after protein loading (Morita et al. 2005); monocyte/macrophage influx impaired in Hspg23/3Col18a1−/– mice in a model of renal ischemia/reperfusion (Celie et al. 2007). | ||
Secreted as CSPG in some tissues (Danielson et al. 1992; Govindraj et al. 2002; Vogl-Willis and Edwards 2004; West et al. 2006), but relationship of CSPG isoform to phenotypes not established. | ||
Prg1 | Serglycin | Null allele: viable; secretory granule defects in mast cells (Abrink et al. 2004); dense core formation is defective in mast cell granules (Henningsson et al. 2006); defective secretory granule maturation and granzyme B storage in cytotoxic T cells (Grujic et al. 2005); no effect on macrophages (Zernichow et al. 2006); platelets and megakaryocytes contain unusual scroll-like membranous inclusions (Woulfe et al. 2008); enlargement of multiple lymphoid organs, decrease in the proportion of CD4+ cells, more pronounced airway inflammatory response in older mice (Wernersson et al. 2009); increased virulence of Klebsiella pneumoniae (Niemann et al. 2007); defective regulation of antiviral CD8+ T-cell responses (Grujic et al. 2008). |
Agrn | Agrin | Null allele: embryonic lethal; reduced number, size, and density of postsynaptic acetylcholine receptor aggregates in muscles; abnormal intramuscular nerve branching and presynaptic differentiation (Gautam et al. 1996,1999); smaller brains (Serpinskaya et al. 1999); abnormal development of interneuronal synapses (Gingras et al. 2007); increased resistance to excitotoxic injury (Hilgenberg et al. 2002); reduced number of cortical presynaptic and postsynaptic specializations (Ksiazek et al. 2007). |
Floxed allele: Inactivation in podocytes does not affect glomerular charge selectivity or glomerular architecture (Harvey et al. 2007). | ||
Col18a1 | Collagen XVIII | Null allele: viable; increased microvascular growth (Li and Olsen 2004); increased angiogenesis associated with atherosclerotic plaques (Moulton et al. 2004); delayed regression of blood vessels in the vitreous along the surface of the retina after birth and lack of or abnormal outgrowth of retinal vessels (Fukai et al. 2002); larger choroidal neovascularization lesions and increased vascular leakage (Marneros et al. 2007); accelerated healing and vascularization rate of excisional dorsal skin wounds (Seppinen et al. 2008); anomalous anastomoses of vasculature; disruption of the posterior iris pigment epithelial cell layer with release of melanin granules, severe thickening of the stromal iris basement membrane zone (Marneros and Olsen 2003); increase in the amount of retinal astrocytes (Hurskainen et al. 2005); more severe glomerular and tubulointerstitial injury in induced anti-GBM glomerulonephritis (Hamano et al. 2010); monocyte/macrophage influx impaired in Hspg23/3Col18a1−/– mice in a model of renal ischemia/reperfusion (Celie et al. 2007); mild chylomicronemia (Bishop et al. 2010). |
Table 3.
Mouse mutants altered in HS biosynthesisGene | Enzyme | Phenotype |
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Xt1 | Xylosyltransferase-1 | No mutants reported. |
Xt2 | Xylosyltransferase-2 | Null allele: viable; polycystic kidney and livers (Condac et al. 2007). |
GalTI (β4GalT7) | Galactosyltransferase I | Human mutants: defective chondroitin substitution of decorin and biglycan in an Ehlers–Danlos patient (Gotte and Kresse 2005; Seidler et al. 2006). |
GalTII (β3GalT6) | Galactosyltransferase II | No mutants reported. |
Glcat1 | Glucuronyltransferase I | Null allele: embryonic lethal (4–8-cell stage) (Izumikawa et al. 2010). |
Extl3 | N-acetylglucosaminyl transferase I | Floxed allele: Inactivation in islets decreases growth and insulin secretion (Takahashi et al. 2009). |
Ext1/Ext2 | HS Copolymerase (N-acetylglucosaminyl-glucuronyltransferase) | Null allele: embryonic lethal (E6-7.5); lack of mesoderm differentiation (Lin et al. 2000; Stickens et al. 2005); heterozygotes develop rib growth plate exostoses (Stickens et al. 2005; Zak et al. 2011); unaltered vascular permeability in heterozygous mice (Xu et al. 2010a). |
Floxed allele of Ext1: defective brain morphogenesis and midline axon guidance after nestin-Cre inactivation (Inatani et al. 2003); no effect on adaptive immune response in CD15Cre mice (Garner et al. 2008); altered T-cell and dendritic cell homing to lymph nodes in Tie2Cre mice (Bao et al. 2010); rib growth plate exostosis formation in Col2Cre mice (Jones et al. 2010; Matsumoto et al. 2010; Zak et al. 2011). | ||
Ndst1 | N-acetylglucosaminyl N-deacetylase/N-sulfotransferase-1 | Null allele: Perinatal lethal; lung hypoplasia, defective forebrain, lens, and skull development (Fan et al. 2000; Ringvall et al. 2000; Grobe et al. 2005; Pan et al. 2006). |
Floxed allele: decreased chemokine transcytosis and presentation and neutrophil infiltration in Tie2Cre mice (Wang et al. 2005); decreased allergen-induced airway hyperresponsiveness and inflammation because of reduction in recruitment of eosinophils, macrophages, neutrophils, and lymphocytes in Tie2Cre mice (Zuberi et al. 2009); decreased pathological angiogenesis in Tie2Cre mice (Fuster et al. 2007); decreased vascular VEGF-induced hyperpermeability (Xu et al. 2010a); decreased vascular smooth muscle cell proliferation, vessel size, and vascular remodeling after arterial injury in SM22αCre mice (Adhikari et al. 2010a); mild effect on T-cell response in Tie2Cre;Ndst2−/−mice (Garner et al. 2008); defective lacrimal gland development and Fgf10-Fgfr2b complex formation and signaling in LeCre mice (Pan et al. 2008); defective lobuloalveolar development in mammary gland (Crawford et al. 2010). | ||
Ndst2 | N-acetylglucosaminyl N-deacetylase/N-sulfotransferase-2 | Null allele: viable; mast cell deficiency and defective storage of proteases (Forsberg et al. 1999; Humphries et al. 1999); compounding mutation with Ndst1 reduces l-selectin interactions (Wang et al. 2005). |
Ndst3 | N-acetylglucosaminyl N-deacetylase/N-sulfotransferase-3 | Null allele: viable; floxed allele available (Pallerla et al. 2008). |
Ndst4 | N-acetylglucosaminyl N-deacetylase/N-sulfotransferase-4 | No mutants reported. |
Glce | Uronyl C5 epimerase | Null allele: perinatal lethal; renal agenesis (Li et al. 2003). |
H2st | Uronyl 2-O-sulfotransferase | Null allele: perinatal lethal; renal agenesis; skeletal and ocular defects (Bullock et al. 1998; Merry et al. 2001); defective cerebral cortical development (McLaughlin et al. 2003); altered lacrimal gland development (Qu et al. 2011). |
Floxed allele: altered lipoprotein clearance in AlbCre mice (Stanford et al. 2010); altered branching morphogenesis in the mammary gland (Garner et al. 2011). | ||
H3st1 | Glucosaminyl 3-O-sulfotransferase 1 | Null allele: partially penetrant lethality; no alteration in coagulation (HajMohammadi et al. 2003); fertility defects because of impaired ovarian function and placenta development (Shworak et al. 2002; HajMohammadi et al. 2003). |
H3st2 | Glucosaminyl 3-O-sulfotransferase 2 | Null allele; viable; no neuronal phenotype (Hasegawa and Wang 2008). |
H3st3 | Glucosaminyl 3-O-sulfotransferase 3 | No mutants reported. |
H3st4 | Glucosaminyl 3-O-sulfotransferase 4 | No mutants reported. |
H3st5 | Glucosaminyl 3-O-sulfotransferase 5 | No mutants reported. |
H3st6 | Glucosaminyl 3-O-sulfotransferase 6 | No mutants reported. |
H6st1 | Glucosaminyl 6-O-sulfotransferase 1 | Null allele: embryonic lethal (Habuchi et al. 2007; Sugaya et al. 2008). |
Gene trap allele: embryonic lethal; retinal axon guidance defects (Pratt et al. 2006). | ||
Floxed allele: systemic inactivation embryonic lethal (Izvolsky et al. 2008); no change in plasma triglycerides in AlbCre mice (Stanford et al. 2010). | ||
H6st2 | Glucosaminyl 6-O-sulfotransferase 2 | Null allele: viable (Sugaya et al. 2008); HS6ST-2, but not HS6ST-1, morphants in zebrafish show abnormalities in the branching morphogenesis of the caudal vein (Chen et al. 2005). |
H6st3 | Glucosaminyl 6-O-sulfotransferase 3 | No mutants reported. |
Hpa | Heparanase, transgene | Accelerated wound angiogenesis, enhanced delayed type hypersensitivity response (Zcharia et al. 2005; Edovitsky et al. 2006; Ilan et al. 2006); accumulation of intracellular crystals of protein Ym1 in macrophages (Waern et al. 2010); resistance to amyloid protein A amyloidosis (Li et al. 2005); age-related enlargement of lymphoid tissue and altered leukocyte composition (Wernersson et al. 2009). |
Hpa | Heparanase | Null allele: viable; altered MMP-2 and MMP-14 expression (Zcharia et al. 2009). |
Sulf1 | Endo-6-sulfatase 1 | Null allele: viable; esophageal defect (Ai et al. 2007; Ratzka et al. 2008); enhanced osteoarthritis, MMP-13, ADAMTS-5, and noggin elevated, col2a1 and aggrecan reduced in cartilage and chondrocytes (Otsuki et al. 2010). |
Sulf2 | Endo-6-sulfatase 2 | Null allele: viable; behavioral defects (Lamanna et al. 2006); enhanced osteoarthritis, MMP-13, ADAMTS-5, and noggin elevated, col2a1 and aggrecan reduced in cartilage and chondrocytes (Otsuki et al. 2010). |
Gene trap allele: Sulf2GT(pGT1TMpfs)155Ska, no phenotype (Lum et al. 2007). |
- HSPGs are present in basement membranes (perlecan, agrin, and collagen XVIII), where they collaborate with other matrix components to define basement membrane structure and to provide a matrix for cell migration.
- HSPGs are found in secretory vesicles, most notably serglycin, which plays a role in packaging granular contents, maintaining proteases in an active state, and regulating various biological activities after secretion such as coagulation, host defense, and wound repair.
- HSPGs can bind cytokines, chemokines, growth factors, and morphogens, protecting them against proteolysis. These interactions provide a depot of regulatory factors that can be liberated by selective degradation of the HS chains. They also facilitate the formation of morphogen gradients essential for cell specification during development and chemokine gradients involved in leukocyte recruitment and homing.
- HSPGs can act as receptors for proteases and protease inhibitors regulating their spatial distribution and activity.
- Membrane proteoglycans cooperate with integrins and other cell adhesion receptors to facilitate cell-ECM attachment, cell–cell interactions, and cell motility.
- Membrane HSPGs act as coreceptors for various tyrosine kinase-type growth factor receptors, lowering their activation threshold or changing the duration of signaling reactions.
- Membrane HSPGs act as endocytic receptors for clearance of bound ligands, which is especially relevant in lipoprotein metabolism in the liver and perhaps in the formation of morphogen gradients during development.
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Recent advances in the characterization of the archaeal DNA replication system together with comparative genomic analysis have led to the identification of several previously uncharacterized archaeal proteins involved in replication and currently reveal a nearly complete correspondence between the components of the archaeal and eukaryotic replication machineries. It can be inferred that the archaeal ancestor of eukaryotes and even the last common ancestor of all extant archaea possessed replication machineries that were comparable in complexity to the eukaryotic replication system. The eukaryotic replication system encompasses multiple paralogs of ancestral components such that heteromeric complexes in eukaryotes replace archaeal homomeric complexes, apparently along with subfunctionalization of the eukaryotic complex subunits. In the archaea, parallel, lineage-specific duplications of many genes encoding replication machinery components are detectable as well; most of these archaeal paralogs remain to be functionally characterized. The archaeal replication system shows remarkable plasticity whereby even some essential components such as DNA polymerase and single-stranded DNA-binding protein are displaced by unrelated proteins with analogous activities in some lineages.Double-stranded DNA is the molecule that carries genetic information in all cellular life-forms; thus, replication of this genetic material is a fundamental physiological process that requires high accuracy and efficiency (Kornberg and Baker 2005). The general mechanism and principles of DNA replication are common in all three domains of life—archaea, bacteria, and eukaryotes—and include recognition of defined origins, melting DNA with the aid of dedicated helicases, RNA priming by the dedicated primase, recruitment of DNA polymerases and processivity factors, replication fork formation, and simultaneous replication of leading and lagging strands, the latter via Okazaki fragments (Kornberg and Baker 2005; Barry and Bell 2006; Hamdan and Richardson 2009; Hamdan and van Oijen 2010). Thus, it was a major surprise when it became clear that the protein machineries responsible for this complex process are drastically different, especially in bacteria compared with archaea and eukarya. The core components of the bacterial replication systems, such as DNA polymerase, primase, and replication helicase, are unrelated or only distantly related to their counterparts in the archaeal/eukaryotic replication apparatus (Edgell 1997; Leipe et al. 1999).The existence of two distinct molecular machines for genome replication has raised obvious questions on the nature of the replication system in the last universal common ancestor (LUCA) of all extant cellular life-forms, and three groups of hypotheses have been proposed (Leipe et al. 1999; Forterre 2002; Koonin 2005, 2006, 2009; Glansdorff 2008; McGeoch and Bell 2008): (1) The replication systems in Bacteria and in the archaeo–eukaryotic lineage originated independently from an RNA-genome LUCA or from a noncellular ancestral state that encompassed a mix of genetic elements with diverse replication strategies and molecular machineries. (2) The LUCA was a typical cellular life-form that possessed either the archaeal or the bacterial replication apparatus in which several key components have been replaced in the other major cellular lineage. (3) The LUCA was a complex cellular life-form that possessed both replication systems, so that the differentiation of the bacterial and the archaeo–eukaryotic replication machineries occurred as a result of genome streamlining in both lines of descent that was accompanied by differential loss of components. With regard to the possible substitution of replication systems, a plausible mechanism could be replicon takeover (Forterre 2006; McGeoch and Bell 2008). Under the replicon takeover hypothesis, mobile elements introduce into cells a new replication system or its components, which can displace the original replication system through one or several instances of integration of the given element into the host genome accompanied by inactivation of the host replication genes and/or origins of replication. This scenario is compatible with the experimental results showing that DNA replication DNA in Escherichia coli with an inactivated DnaAgene or origin of replication can be rescued by the replication apparatus of R1 or F1 plasmids integrated into the bacterial chromosome (Bernander et al. 1991; Koppes 1992). Furthermore, genome analysis suggests frequent replicon fusion in archaea and bacteria (McGeoch and Bell 2008); in particular, such events are implied by the observation that in archaeal genomes, genes encoding multiple paralogs of the replication helicase MCM and origins of replication are associated with mobile elements (Robinson and Bell 2007; Krupovic et al. 2010). Replicon fusion also is a plausible path from a single origin of replication that is typical of bacteria to multiple origins present in archaea and eukaryotes. However, all the evidence in support of frequent replicon fusion and the plausibility of replicon takeover notwithstanding, there is no evidence of displacement of the bacterial replication apparatus with the archaeal version introduced by mobile elements, or vice versa, displacement of the archaeal machinery with the bacterial version, despite the rapid accumulation of diverse bacterial and archaeal genome sequences. Thus, the displacement scenarios of DNA replication machinery evolution are so far not supported by comparative genomic data.Regardless of the nature of the DNA replication system (if any) in the LUCA and the underlying causes of the archaeo–bacterial dichotomy of replication machineries, the similarity between the archaeal and eukaryotic replication systems is striking (Leipe et al. 1999; Bell and Dutta 2002; Bohlke et al. 2002; Kelman and White 2005; Barry and Bell 2006). Thus, the archaeal replication system appears to be an ancestral version of the eukaryotic system and hence a good model for functional and structural studies aimed at gaining mechanistic insights into eukaryotic replication.
Open in a separate windowFor eukaryotic genes in Homo sapiens and Saccharomyces cerevisiae, gene names are indicated. Archaeal genes are denoted as in Barry and Bell (2006) or as introduced here.aNot confidently traced to LACA.In the last few years, there has been substantial progress in the study of the archaeal replication systems that has led to an apparently complete delineation of all proteins that are essential for replication (Berquist et al. 2007; Beattie and Bell 2011a; MacNeill 2011). The combination of experimental, structural, and bioinformatics studies has led to the discovery of archaeal homologs (orthologs) for several components of the replication system that have been previously deemed specific for eukaryotes (Barry and Bell 2006; MacNeill 2010, 2011; Makarova et al. 2012). Furthermore, complex evolutionary events that involve multiple lineage-specific duplications, domain rearrangements, and gene loss, and in part seem to parallel the evolution of the evolution of the replication system in eukaryotes, have been delineated for a variety of replication proteins in several archaeal lineages (Tahirov et al. 2009; Chia et al. 2010; Krupovic et al. 2010). Here we summarize these findings and present several additional case studies that show the complexity of evolutionary scenarios for the components of the archaeal replication machinery and new aspects of their relationship with the eukaryotic replication system. 相似文献
Table 1.
The relationship between archaeal and eukaryotic replication systemsArchaea (projection for LACA) | Eukaryotes (projection for LECA) | Comments |
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ORC complex | ||
arORC1 | Orc1, Cdc6 | In LACA the ORC/Cdc6 complex probably consisted of two distinct subunits, and in LECA of six distinct. Both complexes might possess additional Orc6 and Cdt1 components. |
arORC2 | Orc2, Orc3, Orc4, Orc5 | |
TFIIB or homologa | Orc6 | |
WhiP or other wHTH proteina | Cdt1 | |
CMG complex | ||
Archaeal Cdc45/RecJ | Cdc45 | In many archaea and eukaryotes, CDC45/RecJ apparently contain inactive DHH phosphoesterase domains. The RecJ family is triplicated in euryarchaea, and some of the paralogs could be involved in repair. MCM is independently duplicated in several lineages of euryarchaea. |
Mcm | Mcm2, Mcm3, Mcm4, Mcm5, Mcm6, Mcm7 | |
Gins23 | Gins2, Gins3 | |
Gins15 | Gins1, Gins5 | |
Inactivated MCM homologa | Mcm10 | |
CMG activation factors | ||
— | RecQ/Sld2 | There is no evidence that kinases and phosphatases in archaea are directly involved in replication, although they probably regulate cell division. |
— | Treslin/Sld3 | |
— | TopBP1/Dpb11 | |
STK | CDK, DDK | |
PP2C | PP2C | |
Primases | ||
Prim1/p48 | PriS | In eukaryotes, Pol α is involved in priming by adding short DNA fragments to RNA primers. In archaea, DnaG might be involved in priming specifically on the lagging strand. |
Prim2a/p58 | PriL | |
DnaG | — | |
Polymerases | ||
PolB3 | Pol α, Pol δ, Pol ζ | No eukaryotic homologs of DP2 are known, but Zn fingers of Pol ε are apparently derived from DP2. |
PolB1 | Pol ε | |
DP1 | B subunits of Pol α, Pol δ, Pol ζ, Pol ε | |
DP2 | — | |
DNA polymerase sliding clamp and clamp loader | ||
RFCL | RFC1 | Eukaryotes have additional duplications of both RFCs and PCNA involved in checkpoint complexes (Rad27 and Rad1, Rad9, Hus1, respectively). |
RFCS | RFC2, RFC3, RFC4, RFC4 | |
PCNA | PCNA | |
Primer removal and gap closure | ||
RNase H2 | RNase II | There is a triplication of ligases (LigI, LigIII, LigIV) in eukaryotes, but only LigI is directly involved in replication. In a few Halobacteria, ATP-dependent ligase is replaced by NAD-dependent ligase. |
Fen1 | Fen1/EXO1, Rad2, Rad27 | |
Lig1 | Lig1 | |
SSB | ||
arRPA1_long | Rpa1 | In Thermoproteales, RPA is displaced by the non-homologous ThermoSSB; two short RPA forms in many euryarchaea; expansion of short RPA forms in Halobacteria. |
arRPA1_short and RPA2 | Rpa2 | |
arCOG05741a | Rpa3 |
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David M. Feliciano Angélique Bordey Luca Bonfanti 《Cold Spring Harbor perspectives in biology》2015,7(10)
Two decades after the discovery that neural stem cells (NSCs) populate some regions of the mammalian central nervous system (CNS), deep knowledge has been accumulated on their capacity to generate new neurons in the adult brain. This constitutive adult neurogenesis occurs throughout life primarily within remnants of the embryonic germinal layers known as “neurogenic sites.” Nevertheless, some processes of neurogliogenesis also occur in the CNS parenchyma commonly considered as “nonneurogenic.” This “noncanonical” cell genesis has been the object of many claims, some of which turned out to be not true. Indeed, it is often an “incomplete” process as to its final outcome, heterogeneous by several measures, including regional location, progenitor identity, and fate of the progeny. These aspects also strictly depend on the animal species, suggesting that persistent neurogenic processes have uniquely adapted to the brain anatomy of different mammals. Whereas some examples of noncanonical neurogenesis are strictly parenchymal, others also show stem cell niche-like features and a strong link with the ventricular cavities. This work will review results obtained in a research field that expanded from classic neurogenesis studies involving a variety of areas of the CNS outside of the subventricular zone (SVZ) and subgranular zone (SGZ). It will be highlighted how knowledge concerning noncanonical neurogenic areas is still incomplete owing to its regional and species-specific heterogeneity, and to objective difficulties still hampering its full identification and characterization.The central nervous system (CNS) of adult mammals is assembled during developmental neurogenesis, and its architectural specificity is maintained through a vast cohort of membrane-bound and extracellular matrix molecules (Gumbiner 1996; Bonfanti 2006). Although CNS structure is sculpted by experience-dependent synaptic plasticity at different postnatal developmental stages (critical periods) (see Sale et al. 2009) and, to a lesser extent, during adulthood (Holtmaat and Svoboda 2009), the neural networks are rather stabilized in the “mature” nervous tissue (Spolidoro et al. 2009). The differentiated cellular elements forming adult neural circuitries remain substantially unchanged in terms of their number and types, because cell renewal/addition in the CNS is very low. This situation is intuitive because connectional, neurochemical, and functional specificities are fundamental features of the mature CNS in highly complex brains, allowing specific cell types to be connected and to act in a relatively invariant way (Frotscher 1992).Since the discovery of neural stem cells (NSCs) (Reynolds and Weiss 1992), we realized that the aforementioned rules of CNS stability have a main exception in two brain regions: the forebrain subventricular zone (SVZ) (Lois and Alvarez-Buylla 1994) and the hippocampal subgranular zone (SGZ) (Gage 2000). These “adult neurogenic sites” are remnants of the embryonic germinal layers (although indirectly for the SGZ, which forms ectopically from the embryonic germinative matrix), which retain stem/progenitor cells within a special microenvironment, a “niche,” allowing and regulating NSC activity (Kriegstein and Alvarez-Buylla 2009). In addition, the areas of destination (olfactory bulb and dentate gyrus) reached by neuroblasts generated within these neurogenic sites harbor specific, not fully identified yet, environmental signals allowing the integration of young, newborn neurons. These two “canonical” sites of adult neurogenesis have been found in all animal species studied so far, including humans (reviewed in Lindsey and Tropepe 2006; Bonfanti and Ponti 2008; Kempermann 2012; Grandel and Brand 2013). Although in several classes of vertebrates including fish, amphibians, and reptiles, adult neurogenesis is widespread in many areas of the CNS (Zupanc 2006; Chapouton et al. 2007; Grandel and Brand 2013), in mammals, the vast majority of the brain and spinal cord regions out of the germinal-layer-derived neurogenic sites are commonly referred to as “nonneurogenic parenchyma” (Sohur et al. 2006; Bonfanti and Peretto 2011; Bonfanti and Nacher 2012). However, this viewpoint has changed during the last few years. New examples of cell genesis, involving both neurogenesis and gliogenesis, have been shown to occur in the so-called nonneurogenic regions of the mammalian CNS (Horner et al. 2000; Dayer et al. 2005; Kokoeva et al. 2005; Luzzati et al. 2006; Ponti et al. 2008; reviewed in Butt et al. 2005; Nishiyama et al. 2009; Migaud et al. 2010; Bonfanti and Peretto 2011), suggesting that structural plasticity involving de novo neural cell genesis could be more widespread than previously thought. Apart from their temporal persistence (some of them represent examples of delayed developmental neurogenesis, which persist postnatally; see below), neurogliogenic processes vary as to their regional localization, origin, and final outcome. In this review, “noncanonical” neurogenic processes occurring in adult mammals will be reviewed by underlining their heterogeneity across the species and their differences in intensity and outcome with respect to canonical neurogenic sites.
Open in a separate windowUnshaded rows, spontaneous (constitutive) neurogenesis; shaded rows, experimentally induced neurogenesis (growth factor infusion, lesion, etc.). No functional integration has been shown to occur in any of the studies reported here.aNeuronal differentiation of newborn cells has been well documented; in all other cases, neurogenesis has been shown only until the cell-specification step, and/or assessed with less accurate analyses (reslicing not performed, neuronal differentiation not clearly shown, very few cells shown in figures, insufficient or absent quantification).bNeurogenesis reported in this region has been denied by subsequent reports. Only a set of studies are reported; gliogenesis is not considered (data modified from Bonfanti and Peretto 2011). 相似文献
Table 1.
Main sites of noncanonical neurogenesis in the mammalian brainRats | Mice | Rabbits | Monkeys | |
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Neocortex | Gould et al. 2001 Dayer et al. 2005a Tamura et al. 2007 | Shapiro et al. 2009 | Gould et al. 1999, 2001 Bernier et al. 2002 | |
Nakatomi et al. 2002a Pencea et al. 2001 Ohira et al. 2010a | Magavi et al. 2000a Chen et al. 2004a | Vessal and Darian-Smith 2010a | ||
Corpus callosum | Pencea et al. 2001 | |||
Piriform cortexb | Pekcec et al. 2006 | Shapiro et al. 2007 | Bernier et al. 2002 | |
Olfactory tubercle | Shapiro et al. 2009 | Bedard et al. 2002b | ||
Striatum | Dayer et al. 2005a | Shapiro et al. 2009 | Luzzati et al. 2006a | Bedard et al. 2002a; 2006a |
Arvidsson et al. 2002a Pencea et al. 2001 Liu et al. 2009a | Goldowitz and Hamre 1998a Cho et al. 2007a | |||
Septum | Pencea et al. 2001 | |||
Amygdala | Shapiro et al. 2009 | Luzzati et al. 2006a | Bernier et al. 2002 | |
Hippocampus (Ammon’s horn) | Rietze et al. 2000 | |||
Nakatomi et al. 2002a | ||||
Thalamus | Pencea et al. 2001 | |||
Hypothalamus | Xu et al. 2005 | Kokoeva et al. 2007 | ||
Xu et al. 2005a Pencea et al. 2001 Matsuzaki et al. 2009 Perez-Martin et al. 2010 | Kokoeva et al. 2005a Pierce and Xu 2010 | |||
Substantia nigra | Zhao et al. 2003 Zhao and Janson Lang 2009 | |||
Zhao et al. 2003 | ||||
Cerebellum | Ponti et al. 2008a | |||
Brain stem | Bauer et al. 2005 | |||
Bauer et al. 2005 |
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Embryonic stem cells (ESCs) can generate all of the cell types found in the adult organism. Remarkably, they retain this ability even after many cell divisions in vitro, as long as the culture conditions prevent differentiation of the cells. Wnt signaling and β-catenin have been shown to cause strong effects on ESCs both in terms of stimulating the expansion of stem cells and stimulating differentiation toward lineage committed cell types. The varied effects of Wnt signaling in ESCs, alongside the sometimes unconventional mechanisms underlying the effects, have generated a fair amount of controversy and intrigue regarding the role of Wnt signaling in pluripotent stem cells. Insights into the mechanisms of Wnt function in stem cells can be gained by examination of the causes for seemingly opposing effects of Wnt signaling on self-renewal versus differentiation.For a single-cell embryo to eventually form an adult organism of trillions of cells, some cells in the early mammalian embryo must be able to generate all cell lineages in the animal. The potential to make all adult cell types defines the property of pluripotency, and it is maintained in proliferating cells through a process called self-renewal. As cells become specified to contribute to particular lineages, they typically lose the ability to make cell types from distinct lineages (Waddington 1957; Hochedlinger and Plath 2009). As such, pluripotency is lost during the initial steps of lineage commitment that occur during gastrulation (Beddington 1982, 1983; Lawson and Pedersen 1987; Lawson et al. 1991), which is a process that coordinates the generation of adult cell lineages with the elaboration of a basic three-dimensional body structure (Heisenberg and Solnica-Krezel 2008). In the mouse, pluripotency can be tested with various experiments; the gold standard is the injection of cells into a blastocyst-staged embryo followed by contribution to a diversity of cell types in the chimeric animal or chimeric embryo after gastrulation. Cells are typically considered to have been pluripotent only if they contributed to all three germ layers (endoderm, mesoderm, and ectoderm).Embryonic stem cells (ESCs) are generated in vitro by outgrowths from a preimplantation-staged embryo, frequently a blastocyst. Pluripotent cells from the inner cell mass (ICM) of the blastocyst proliferate to form colonies, which can be expanded into ESC cultures. When culture conditions for in vitro propagation of mouse ESCs (mESCs) were first discovered more than 30 years ago (Evans and Kaufman 1981; Martin 1981), the critical achievement was finding conditions supporting indefinite ESC self-renewal, that is, maintenance of pluripotency following cell division. Compared with the other cell systems discussed below in this article, mESCs ostensibly display the greatest capacity for self-renewal and the highest ability to maintain pluripotency. As such, mESCs are typically thought to represent a primitive, or “naive,” cellular state in the early embryo.Several culture conditions can support self-renewal of mESCs. Initially, ESCs were grown in serum containing media atop a layer of mitotically inactivated fibroblasts, called feeder cells (Evans and Kaufman 1981). Feeder cells secrete the LIF cytokine, which binds a transmembrane receptor complex consisting of LIFR and gp130 proteins (Gearing et al. 1991; Gearing and Bruce 1992; Davis et al. 1993). LIF binding activates Jak/Stat signaling and Stat3 phosphorylation, which promotes ESC self-renewal (Niwa et al. 1998; Matsuda et al. 1999). Convincing proof of LIF’s importance for self-renewal in vitro was shown when recombinant LIF protein was shown to be sufficient to replace feeder cells in ESC cultures (Smith et al. 1988; Williams et al. 1988; Nichols et al. 1990).Essentially the same feeder cells can be used for both mESCs and human ESCs (hESCs); however, discrete activities of the feeders in terms of the cytokines they release are needed to effect optimal self-renewal for each cell. The LIF cytokine important for mESC self-renewal did not stimulate hESC self-renewal (Thomson et al. 1998). Instead, ERK signaling downstream from Fgf2 must accompany a feeder layer in serum-containing media for optimal hESC self-renewal (Xu et al. 2005). Interestingly, recombinant Fgf2 by itself could not replace feeders, and Fgf2 has been suggested to work in part by stimulating feeders to produce Activin/Nodal ligands; the combination of Fgf2 and Nodal/Activin is sufficient to support hESC self-renewal in serum-free chemically defined culture conditions (Vallier et al. 2004, 2009; James et al. 2005).Clear differences exist between mESCs and hESCs. The colonies adopt different morphologies, they require distinct culture conditions for self-renewal, and they have significantly different gene expression signatures (Brons et al. 2007; Tesar et al. 2007). Mouse EpiSCs are made from the epiblast of postimplantation-staged embryos between embryonic days 5.5 (E5.5) and E6.5 of embryogenesis (Brons et al. 2007; Tesar et al. 2007; Han et al. 2010). Lineage specification of pluripotent epiblast cells begins soon after formation of a cup-like structure, and at E6.5, the cells in the epiblast begin to be specified to primary cell lineages during gastrulation. The in vivo cellular environment for ICM cells and postimplantation epiblast cells is considerably different, and it is not surprising that EpiSCs and mESCs display many different characteristics (Xu et al. 2010). However, it was somewhat surprising that EpiSCs share many characteristics with hESCs, including a common colony morphology, Fgf2 + Activin A culture conditions, and gene expression signatures (Brons et al. 2007; Tesar et al. 2007). Like mESCs and hESCs, EpiSCs pass pluripotency tests for in vitro differentiation and teratoma formation. Whereas mESC can efficiently convert (i.e., differentiate) into EpiSC-like cells when switched to Fgf2/Activin A media (Hanna et al. 2009; Greber et al. 2010), EpiSCs required genetic manipulation or reprogramming for efficient conversion to mES-like cells (Guo et al. 2009; Hanna et al. 2009; Greber et al. 2010; Guo and Smith 2010). Many investigators consider hESCs and mouse EpiSCs to be primed for differentiation as they reside in a less primitive differentiation state relative to the naive state of pluripotency in mESCs.
Open in a separate windowThree pluripotent cell systems are compared with respect to characteristics that describe their epigenetic state of pluripotency. See text for details. 相似文献
Table 1.
Pluripotent stem cell states: Naive and primedMouse ESC | Human ESC | Mouse EpiSC | |
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Effects of culture conditions | |||
Serum + Lif Wnt3a/GSK3inhibitor Fgf2 + Activin A | Self-renewal Self-renewal EpiSC | Differentiation Differentiation Self-renewal | Differentiation Differentiation Self-renewal |
Gene expression profiles | |||
Oct4, Sox2, Nanog Sox17, Eomes, Fgf5 Klf4, Rex1, Stella | High Low High | High High Low | High High Low |
Activity in pluripotency tests | |||
Embryoid body Teratoma formation Blastocyst injection Tetraploid complementation | Pass Pass Pass Pass | Pass Pass Not determined Not determined | Pass Pass Poor Not determined |
Epigenetic state | Naive | Primed | Primed |
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Genital coevolution between the sexes is expected to be common because of the direct interaction between male and female genitalia during copulation. Here we review the diverse mechanisms of genital coevolution that include natural selection, female mate choice, male–male competition, and how their interactions generate sexual conflict that can lead to sexually antagonistic coevolution. Natural selection on genital morphology will result in size coevolution to allow for copulation to be mechanically possible, even as other features of genitalia may reflect the action of other mechanisms of selection. Genital coevolution is explicitly predicted by at least three mechanisms of genital evolution: lock and key to prevent hybridization, female choice, and sexual conflict. Although some good examples exist in support of each of these mechanisms, more data on quantitative female genital variation and studies of functional morphology during copulation are needed to understand more general patterns. A combination of different approaches is required to continue to advance our understanding of genital coevolution. Knowledge of the ecology and behavior of the studied species combined with functional morphology, quantitative morphological tools, experimental manipulation, and experimental evolution have been provided in the best-studied species, all of which are invertebrates. Therefore, attention to vertebrates in any of these areas is badly needed.Of all the evolutionary interactions between the sexes, the mechanical interaction of genitalia during copulation in species with internal fertilization is perhaps the most direct. For this reason alone, coevolution between genital morphologies of males and females is expected. Morphological and genetic components of male and female genitalia have been shown to covary in many taxa (Sota and Kubota 1998; Ilango and Lane 2000; Arnqvist and Rowe 2002; Brennan et al. 2007; Rönn et al. 2007; Kuntner et al. 2009; Tatarnic and Cassis 2010; Cayetano et al. 2011; Evans et al. 2011, 2013; Simmons and García-González 2011; Yassin and Orgogozo 2013; and see examples in Taxa Male structures Female structures Evidence Likely mechanism References Mollusks Land snails (Xerocrassa) Spermatophore-producing organs Spermatophore-receiving organs Comparative among species SAC or female choice Sauder and Hausdorf 2009 Satsuma Penis length Vagina length Character displacement Lock and key Kameda et al. 2009 Arthropods Arachnids (Nephilid spiders) Multiple Multiple Comparative among species SAC Kuntner et al. 2009 Pholcidae spiders Cheliceral apophysis Epigynal pockets Comparative (no phylogenetic analysis) Female choice Huber 1999 Harvestmen (Opiliones) Hardened penes and loss of nuptial gifts Sclerotized pregenital barriers Comparative among species SAC Burns et al. 2013 Millipedes Parafontaria tonominea Gonopod size Genital segment size Comparative in species complex Mechanical incompatibility resulting from Intersexual selection Sota and Tanabe 2010 Antichiropus variabilis Gonopod shape and size Accesory lobe of the vulva and distal projection Functional copulatory morphology Lock and key Wojcieszek and Simmons 2012 Crustacean Fiddler crabs, Uca Gonopode Vulva, vagina, and spermatheca Two-species comparison, shape correspondence Natural selection against fluid loss, lock and key, and sexual selection Lautenschlager et al. 2010 Hexapodes Odonates Clasping appendages Abdominal shape and sensory hairs Functional morphology, comparative among species Lock and key via female sensory system Robertson and Paterson 1982; McPeek et al. 2009 Insects Coleoptera: seed beetles Spiny aedagus Thickened walls of copulatory duct Comparative among species SAC Rönn et al. 2007 Callosobruchus: Callosobruchus maculatus Damage inflicted Susceptibility to damage Full sib/half sib mating experiments SAC Gay et al. 2011 Reduced spines No correlated response Experimental evolution SAC Cayetano et al. 2011 Carabid beetles (Ohomopterus) Apophysis of the endophallus Vaginal appendix (pocket attached to the vaginal apophysis) Cross-species matings Lock and key Sota and Kubota 1998; Sasabi et al. 2010 Dung beetle: Onthophagus taurus Shape of the parameres in the aedagus Size and location of genital pits Experimental evolution Female choice Simmons and García-González 2011 Diptera: Drosophila santomea and D. yakuba Sclerotized spikes on the aedagus Cavities with sclerotized platelets Cross-species matings SAC Kamimura 2012 Drosophila melanogaster species complex Epandrial posterior lobes
Oviscapt pouches Comparative among species SAC or female choice Yassin and Orgogozo 2013 Phallic spikes Oviscapt furrows Cercal teeth, phallic hook, and spines Uterine, vulval, and vaginal shields D. mauritiana and D. sechelia Posterior lobe of the genital arch Wounding of the female abdomen Mating with introgressed lines SAC Masly and Kamimura 2014 Stalk-eyed flies (Diopsidae) Genital process Common spermathecal duct Comparative among species and morphological Female choice Kotrba et al. 2014 Tse-tse flies: Glossina pallidipes Cercal teeth Female-sensing structures Experimental copulatory function Female choice Briceño and Eberhard 2009a,b Phelebotomine: sand flies Aedagal filaments, aedagal sheaths Spermathecal ducts length, base of the duct Comparative among species None specified Ilango and Lane 2000 Heteroptera: Bed bugs (Cimiciidae) Piercing genitalia Spermalege (thickened exosqueleton) Comparative among species SAC Carayon 1966; Morrow and Arnqvist 2003 Plant bugs (Coridromius) Changes in male genital shape External female paragenitalia Comparative among species SAC Tatarnic and Cassis 2010 Waterstriders (Gerris sp.) Grasping appendages Antigrasping appendages Comparative among species SAC Arnqvist and Rowe 2002 Gerris incognitus Grasping appendages Antigrasping appendages Comparative among populations SAC Perry and Rowe 2012 Bee assassins (Apiomerus) Aedagus Bursa copulatrix Comparative among species None Forero et al. 2013 Cave insects (Psocodea), Neotrogla Male genital chamber Penis-like gynosome Comparative among species Female competition (role reversal), coevolution SAC Yoshizawa et al. 2014 Butterflies (Heliconiinae) Thickness of spermatophore wall Signa: Sclerotized structure to break spermatophores Comparative among species SAC Sánchez and Cordero 2014 Fish Basking shark: Cetorhinus maximus Clasper claw Thick vaginal pads Morphological observation None Matthews 1950 Gambusia Gonopodial tips Genital papillae within openings Comparative among species Strong character displacement Langerhans 2011 Poecilia reticulata Gonopodium tip shape Female gonopore shape Comparative among populations SAC Evans et al. 2011 Reptiles Anoles Hemipene shape Vagina shape Shape correspondence, two species Sexual selection Köhler et al. 2012 Several species Hemipene shape Vagina shape Shape correspondence Lock and key, female choice, and SAC Pope 1941; Böhme and Ziegler 2009; King et al. 2009 Asiatic pit vipers Spininess in hemipenes Thickness of vagina wall Two-species comparison None Pope 1941 Garter snake: Thamnophis sirtalis Basal hempene spine Vaginal muscular control Experimental manipulation SAC Friesen et al. 2014 Birds Waterfowl Penis length Vaginal elaboration Comparative among species SAC Brennan et al. 2007 Tinamous Penis length/presence Vaginal elaboration Comparative among species Female choice/natural selection PLR Brennan, K Zyscowski, and RO Prum, unpubl. Mammals Marsupials Bifid penis Two lateral vaginae Shape correspondence None Renfree 1987 Equidna Bifid penis with four rosettes Single vagina splits into two uteri Shape correspondence None Augee et al. 2006; Johnston et al. 2007 Insectivores: Short-tailed shrew: Blarina brevicauda S-shaped curve of the erect penis Coincident curve in the vagina Shape correspondence None Bedford et al. 2004 Common tenrec: Tenrec caudatus Filiform penis (up to 70% of the male’s body length) Internal circular folds in the vagina Length correspondence None Bedford et al. 2004 Rodents: Cape dune mole: Bathyergus suillus Penis and baculum length Vaginal length Allometric relationships within species None Kinahan et al. 2007 Australian hopping mice (Notomys) Spiny penis Derived distal region in the vagina Morphological observation and two-species comparison Copulatory lock Breed et al. 2013 Pig: Sus domesticus Filiform penis end Cervical ridges Artificial insemination Female choice Bonet et al. 2013 Primates: Macaca arctoides Long and filamentous glans Vestibular colliculus (fleshy fold) that partially obstructs the entrance to the vagina Shape correspondence and comparison with close relatives None Fooden 1967