Abstract

C. elegans vulval development is an intensively studied example of animal organogenesis. A network of intercellular signaling, signal transduction, and transcriptional regulation underlies the precise formation of this organ, which is the connection between the hermaphrodite uterus and the outside of the nematode. A single cell of the somatic gonad, the anchor cell, organizes the development of the vulva from epidermal precursors as well as the physical connection of the epidermis with the uterus. WNT signaling acting via the HOX gene lin-39 renders six epidermal precursor cells competent to respond to other developmental signals. The anchor cell induces nearby epidermal precursor cells to generate vulval cells via an epidermal growth factor (EGF) signaling pathway. The precise pattern of vulval precursor cell fates involves the graded action of the EGF signaling and LIN-12 (Notch) mediated lateral signaling. EGF promotes the primary fate while LIN-12 promotes the secondary fate. Both EGF and LIN-12 prevent precursor cells from adopting the tertiary fate, which generates non-specialized epidermis. EGF-receptor and Notch signaling are antagonistic: EGF-receptor signaling leads to down-regulation of the Notch-like receptor LIN-12, while LIN-12 signaling induces negative regulators of EGF-receptor signaling such as MAP kinase phosphatase LIP-1 and the tyrosine kinase ARK-1. The primary precursor cell generates vulE and vulF mature vulval cells; the pattern of vulE and vulF cells requires an additional signal from the anchor cell as well as WNT signaling. The two secondary precursor cells generate vulA, vulB1, vulB2, vulC and vulD cells but in mirror symmetric polar patterns: ABCD and DCBA. The reversed polarity of the posterior secondary precursor cell lineage requires WNT signaling mediated by both Frizzled class and Ryk class WNT-receptors LIN-17 and LIN-18, respectively. A network of transcription factors controls the seven mature adult cell types; these include the LIM domain protein LIN-11, the Pax2/5/8 protein EGL-38, the zinc finger protein LIN-29, and the Nkx6.1/6.2 protein COG-1. The anchor cell also patterns nearby uterine cells, via the DSL ligand LAG-2 and LIN-12, to generate the four uv1 cells that form the tight connection with the vulva. This connection is initiated by the anchor cell, which invades between the vulF cells in a process analogous to invasive behavior of metastatic tumor cells. During this invasion process, the basement membranes between the gonad and body wall are degraded. The extensive information about vulval development in C. elegans has helped it become a paradigmatic case for identifying and studying a variety of regulatory pathways.

Highlights

  • The C. elegans hermaphrodite vulva develops during postembryonic development from ventral epidermal precursors, and connects the developing uterus to the external environment

  • Vulva development represents a well-understood case in which invariant development arises from multiple cell-cell interactions. It is a striking example of tissue remodeling: the formation of a hole at a precise location in an organism. It has been important for the genetic analyses of signaling and signal transduction by epidermal growth factor (EGF)-receptor LET-23 and RAS LET-60;, LIN-12, and WNT, as well as the functions of the SynMuv and mediator proteins

  • Ablation of all six vulval precursor cells (VPCs) in C. elegans did not result in P2.p or P9.p generating vulval progeny (Sulston and White, 1980; compare to Panagrellus redivivus (Sternberg and Horvitz, 1982; see Evolution of development in nematodes closely related to C. elegans), suggesting that only P3.p-P8.p form the "vulval equivalence group." Additional support for this conclusion comes from the observation that mutations that activate the LET-23 or LIN-12 signaling pathways only cause P3.p-P8.p but P2.p or P9.p to adopt vulval fates (Greenwald et al, 1983; Ferguson et al, 1987; Sternberg, 1988)

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Summary

Introduction

The C. elegans hermaphrodite vulva develops during postembryonic (larval) development from ventral epidermal precursors, and connects the developing uterus to the external environment. Vulva development represents a well-understood case in which invariant development arises from multiple cell-cell interactions It is a striking example of tissue remodeling: the formation of a hole at a precise location in an organism. (1) Generation of VPCs: During the L1 and L2 stages, six vulval precursor cells (VPCs) are specified among the 11 Pn.p cells, which are located in the ventral epidermis. (2) Vulval Precursor Patterning: During the L3 stage, a signal from the gonad and signaling among the VPCs specifies three VPCs to generate vulval cells (Figure 2). Phenotypes of vulval development mutants Mutations that affect vulva development often cause defects that are visible in the dissecting microscope. A number of markers are available to help distinguish different fates of VPCs (Burdine et al, 1998; Yoo et al, 2004) and of terminal vulval cells (Inoue et al, 2002)

Generation of vulval precursor cells
Induction of the vulva by the anchor cell
Possible relay induction by LIN-3
Nuclear targets of the LET-23-LET-60-MPK-1 pathway
WNT signaling and induction
Physiological inputs to vulval development
G protein regulation
Zinc regulation
Nuclear negative regulators
LIN-12-mediated lateral signaling
Coupling of LET-23 and LIN-12 signaling
Patterning of adult cell types
10. The vulval-uterine connection
10.3. AC invasion
11.1. Invagination
11.2. Organization of neurons and muscles
12. Concluding remarks
13. Acknowledgments
14. References
82. Abstract
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