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WIREs Dev Biol
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Morphogenesis of the Caenorhabditis elegans vulva

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Abstract Understanding how cells move, change shape, and alter cellular behaviors to form organs, a process termed morphogenesis, is one of the great challenges of developmental biology. Formation of the Caenorhabditis elegans vulva is a powerful, simple, and experimentally accessible model for elucidating how morphogenetic processes produce an organ. In the first step of vulval development, three epithelial precursor cells divide and differentiate to generate 22 cells of 7 different vulval subtypes. The 22 vulval cells then rearrange from a linear array into a tube, with each of the seven cell types undergoing characteristic morphogenetic behaviors that construct the vulva. Vulval morphogenesis entails many of the same cellular activities that underlie organogenesis and tissue formation across species, including invagination, lumen formation, oriented cell divisions, cell–cell adhesion, cell migration, cell fusion, extracellular matrix remodeling, and cell invasion. Studies of vulval development have led to pioneering discoveries in a number of these processes and are beginning to bridge the gap between the pathways that specify cells and their connections to morphogenetic behaviors. The simplicity of the vulva and the experimental tools available in C. elegans will continue to make vulval morphogenesis a powerful paradigm to further our understanding of the largely mysterious mechanisms that build tissues and organs. WIREs Dev Biol 2013, 2:75–95. doi: 10.1002/wdev.87 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Invertebrate Organogenesis > Worms

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The anchor cell (AC) connects the uterine and vulval tissues and patterns cell fates. (a) AC invasion into the vulval epithelium. At the one‐cell P6.p stage (top panel), the AC is positioned dorsal to P6.p (indicated with white bar) and separated from it by basement membrane (green). Following the first vulval precursor cell (VPC) division (second panel), the AC initiates invasion across the basement membrane. By the four‐cell P6.p stage (third panel), a breach is evident in the basement membrane (indicated with arrow), and the AC has contacted the 1° VPCs. The AC remains at the vulval apex following the final VPC division (bottom panel) and the gap in the basement membrane continues to expand beyond the border of the AC membrane (arrows). The AC expresses a reporter for the plextrin homology (PH) domain of phospholipase Cδ fused to mCherry under an AC‐specific cdh‐3 promoter.96 The basement membrane expresses GFP‐tagged laminin β subunit under its own promoter.97 (b) Molecular pathways regulating AC invasion. The transcription factor FOS‐1A is required for invasion, and regulates the expression of the matrix metalloprotease ZMP‐1. The basal (ventral) AC membrane is enriched for cytoskeletal components F‐actin and the INA‐1/PAT‐3 integrin–receptor complex. The UNC‐6/netrin ligand is released by the ventral nerve cord (VNC) and regulates invasion through its receptor UNC‐40/DCC. A vulval cue from the 1° VPCs is also required for complete invasion. Modeled after Ref 98 (c) The AC patterns uterine and vulval fates. The AC expresses LAG‐2/Delta ligand, which signals to the LIN‐12/Notch receptor on six surrounding ventral uterine cells to induce the π fate rather than the default ρ fate. The presence of the AC between the vulF cells is also required for 1° fate patterning.

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Vulval invagination and toroid formation. (a) After the second cell divisions, the vulval precursor cells (VPCs) are arranged in a longitudinal array. The anchor cell (AC) is positioned at the junction of the vulF cells at the vulval midline. Apical domains are in blue here and in other panels. (b) Concurrent with the final cell divisions, the 1° VPCs invaginate by moving dorsally. The vulF occupies the most dorsal position, with vulE positioned ventral to it. (c) VPCs extend apical membrane processes toward the midline and establish junctions with homotypic cells from the contralateral half, forming rings that encircle a tube in the center of the vulval primordium. In this schematic, vulC–vulF have formed rings. Sister vulA cells on each lateral half fuse shortly after the final cell division,8 shown as a single‐cell boundary. (d) Dorsal view of early‐L4 VPCs, showing the lateral migration of vulval cells toward the midline. (e) Invagination is driven by distal VPCs migrating toward the midline along the ventral surface of inner cells, which forces cells to move dorsally.10 Glycosaminoglycans are expressed by the VPCs and are thought to maintain and shape the forming lumen.11,12 (f) As the L4 stage continues, vulval cells continue to migrate and homotypic cells undergo fusions. A uterine lumen forms, and the uterine and vulval epithelia become separated by the thin membrane of the utse syncytium (left differential interference microscopy image). The right image shows labeling of apical junctions with the apical membrane marker AJM‐1::GFP.13 At this stage, the sister cells on each lateral half have fused, and contralateral vulA and vulD cells have fused at the midline. Red arrows indicate apical borders between vulB1, vulB2, vulC, vulE, and vulF cells. (g) Schematic of vulval toroids in late‐L4 after fusion has completed. Gray circles represent nuclei. All homotypic cells fuse except vulB1 and vulB2. For additional images, see Refs 8 and 10 and WormAtlas.7

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Vulval cell divisions. (a) Adult worm at low (left) and high (right) magnification showing components of the reproductive system. Oocytes in the gonad (outlined in red) move in a distal to proximal direction and are fertilized in the spermatheca (Sp). Embryos pass into the uterus (Ut) and undergo the first rounds of cell division. Muscle contractions push embryos through the vulva to the external environment, where embryogenesis continues until hatching. The posterior gonad is shown; the anterior gonad has an identical arrangement. For additional images of the Caenorhabditis elegans reproductive system, see WormAtlas.7 (b)–(e) Cell divisions in the L3 larval stage. Left is schematic diagram; right is differential interference microscopy (DIC) images of live animals. Lateral view with anterior left and dorsal top. (b) The P6.p cell is induced to the 1° vulval precursor cell (VPC) fate, P5.p and P7.p are induced to the 2° VPC fate, and P3.p, P4.p, and P8.p take on the non‐vulval 3° VPC fate. The anchor cell (AC) is located in the uterine epithelium (Ut) and positioned dorsal to P6.p (right DIC image). (c) All six VPCs divide in the mid‐L3 larval stage, after which the 3° VPCs arrest cell divisions and initiate fusion with the hyp7 syncytium. The 1° VPCs differentiate to vulE and vulF cell types; the 2° VPCs differentiate to vulA, vulB, vulC, and vulD cell types. (d) The third VPC divisions take place in mid‐ to late L3 and produce 12 cells in a longitudinal array. (e) The final VPC divisions occur during the L3/L4 molt. vulC, vulE, and vulF cell divisions occur in the transverse (T) orientation, which is indicated by dashed lines in the lineage diagram. vulA and vulB divide in the longitudinal orientation (L), and vulD does not divide (N). In the DIC image, only the longitudinally divided cells and vulD are in the plane of focus. (f) Dorsal view of the vulval primordium following terminal cell divisions, with the AC at the vulval apex. Modeled after Ref 8. For additional schematics of vulval development and a time series of vulval images from the L3/L4 molt to adulthood, see WormAtlas.7 (g) Heterchronic genes regulate the timing of VPC divisions. LIN‐14, acting through the cell‐cycle repressor cki‐1, inhibits cell divisions in L1, and LIN‐28 and HBL‐1 inhibit L2 cell divisions, acting through unknown targets. In L3, the miRNA lin‐4 represses lin‐14 and lin‐28 mRNA translation to promote cell division. Analogously, the miRNAs mir‐48, mir‐84, and mir‐241 redundantly repress hbl‐1 translation.

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Molecular pathways of vulval cell migration. Cells that are proximal to the midline (vulE in this example) express SMP‐1 on the apical membrane, downstream of LET‐60/Ras, LIN‐39/Hox, and the zinc‐finger transcription factor VAB‐23. More distal cells (vulD) express PLX‐1, which regulates cell migrations in part through the Rac GTPase CED‐10 and its GEF UNC‐73. A second pathway involving MIG‐2 also regulates migration. Modeled after Ref. 68.

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Wnt signaling determines the polarity of vulval precursor cell (VPC) cell divisions. (a) In the presence of posterior‐ expressed Wnt ligand egl‐20 and AC‐expressed Wnt ligands lin‐44 and mom‐2, P5.p and P7.p have mirror‐image symmetry in their cell division patterns, which is termed ‘refined polarity’.63 (b) When lin‐44 and mom‐2 are absent, egl‐20 directs a posterior‐oriented ‘ground polarity’, such that both P5.p and P7.p divide in the same orientation. (c) In the absence of lin‐44, mom‐2, and egl‐20, P5.p and P7.p divide with random polarity. This is considered the ‘default polarity’.63

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Attachments of the vulva to other tissues. (a) The vulA cells on the ventral surface contact the hyp7 hypodermal syncytium; vulE cells extend laterally to contact the hypodermal seam cells; and vulF cells contact the uv1 cells and are overlaid by the utse (see Figure 2(f)). Eight vulval muscles, four vm1 and four vm2, control vulval opening. vm1 cells contact the vulva between vulC and vulD toroids, and vm2 cells contact between vulF and the uterus. Modeled after Refs 8 and 16. For additional images of late vulval development, see WormAtlas.7

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Patterning of neuronal connections in the vulval region. Dorsal view of the everted vulva. The two hermaphrodite‐specific (HSN) neurons (shown is the right HSN in green) extend axons ventrally to the nerve cord, then anteriorly to the vulva. The interaction between HSN‐expressed SYG‐1 and vulF‐expressed SYG‐2 serves to guide the future sites of synaptic contact, which occur on vm2 muscle cells (shown are two of four vm2 cells, light blue) and ventral cord (VC) neurons. VC4 and VC5 have cell bodies at the anterior and posterior of the vulval epithelium, respectively, and extend axons around the vulva and dorsally to synapse on vm2 cells. vulF‐expressed BAM‐2 is required to terminate axon branches. Modeled after Refs 123 and 124.

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