Hypodermis

  1) Overview

The epithelial system of C. elegans constitutes two general categories of cells: hypodermis and specialized epithelial cells. The hypodermis is made of the main body syncytium (hyp 7) and smaller hypodermal cells of the head and tail. The specialized epithelial cells secrete parts of the cuticle, direct the formation of specialized structures in the cuticle, and act as support cells (glia) for neuronal sensory receptors and as linker cells to attach the hypodermis to internal tissues while forming various holes in the cuticle.

The hypodermis performs many functions during early development, including establishing the basic body plan, depositing basement membrane components, regulating cell fate specification of neighboring cells, guiding cell and axon migrations, and taking up apoptotic cell bodies by phagocytosis (Johnstone and Barry, 1996; Greenwald, 1997; Michaux et al., 2001). As the animal matures, the hypodermis is also important for storage of nutrients and deposition of stage-specific cuticles (molting), and it provides a barrier function for the pseudocoelomic cavity (Singh and Sulston, 1978; White, 1988; Kramer, 1997; Yochem et al., 1999; see also The Cuticle and Dauer Cuticle). Mutations in genes that affect the development and function of hypodermal cells result in defects in body morphogenesis, muscle development and cuticle structure and function. The mutants can produce  arrested embryos or larvae and adults with dumpy (dpy) and roller (rol) phenotypes (Kramer, 1997; Fay et al., 1999; see also The Cuticle).

Specialized epithelial cells, fall into three categories: (1) seam cells, which are also referred to as the lateral hypodermis (see Seam Cells); (2) interfacial epithelial cells, which are specialized linker cells located at the interface between hypodermis and another type of tissue (see Interfacial Cells); and (3) atypical epithelial cells, which include the XXX cells in the head and the tail spike cells, both of which have transient epithelial roles in embryonic development (see Atypical Cells).

Epithelial cells of C. elegans are tightly held together by zonula adherens (formerly known as belt desmosomes) on their lateral borders, close to the apical surfaces. These junctions wrap around the epithelial cells and provide a seal and a mechanical link to the adjacent cells. They also segregate each cell membrane into two distinct regions: apical and basolateral surfaces (White, 1988; Michaux et al., 2001). In C. elegans, these junctions exhibit features of both adherens and tight junctions (Costa et al., 1998; Bossinger et al., 2001). The apical surfaces of the epithelial cells are bounded by the cuticle, and the basal surfaces are covered by the basal lamina.

The hypodermis and seam cells form multinucleate syncytia that are generated by cell fusions during development (HypTABLE 1). These cell fusions are regulated by diverse signaling mechanisms (Witze and Rothman, 2002; Podbilewicz, 2006).

  2) Embryonic Development of the Hypodermis
			(also see (http://www.wormbook.org/chapters/www_epidermalmorphogenesis/epidermalmorphogenesis.html) in Wormbook)

As in other triploblastic animals, the outer epithelium of C. elegans arises from the ectoderm. This tissue in C. elegans was originally named the hypodermis, although, in more recent literature it is sometimes referred to as the epidermis due to its ectodermal origin (Sulston and Horvitz, 1977; Wright, 1987). For practical purposes, we refer to it as hypodermis, because each hypodermal cell in C. elegans carries the three-letter acronym âhyp.â The hypodermis develops largely from three cell types: embryonically from the AB founder cell and postembryonically from the lateral seam cells and the ventral blast (P) cells. In the embryo, the hypodermis becomes a monolayer of 78 epithelial cells that secrete the cuticle (Sulston et al., 1983). The majority of the hypodermis is generated from the AB founder cell, which has an intrinsic ability to produce hypodermis and neurons. During the third round of AB division, the potential to generate hypodermis is nonequivalently restricted to four daughter cells of the AB granddaughter cells (the posterior two granddaughters of ABa and the anterior two granddaughters of ABp), whereas their sisters primarily become neuronal precursors (HypFIG 1). Of the four AB great-granddaughters, ABalp is later induced by the MS cell to generate the pharynx, whereas the others continue with their major hypodermal fate (Cowan and McIntosh, 1985; Gendreau et al., 1994).

Most of the embryonic hypodermal cells are born around 210-240 minutes after first cleavage at 20-22Â°C and form a posterior dorsal sheet of cells that is organized in six rows (HypFIG 2). This hypodermal sheet eventually spreads to wrap around the embryo until the ventral edges meet and form adherens junctions to close the embryo in a continuous hypodermal layer. The larger 58 cells of the initial dorsal layer of cells are organized in two inner, two middle and two outer rows with 20, 20 and18 cells, respectively, at about 250 minutes after the first cleavage. The remaining, smaller 20 cells (hyp 1-5, three cells of hyp 6, hyp 8-11) at the anterior and posterior will later form the hypodermis of the anterior head and the tail. Between 290 and 340 minutes, the two inner rows of the epithelial sheet migrate towards each other and intercalate to make a single row of cells (HypFIG 2) (Podbilewicz and White, 1994; Williams-Masson et al., 1998; Chisholm and Hardin, 2005; Chin-Sang and Chisholm, 2000; Shemer and Podbilewicz, 2000; Simske and Hardin, 2001). Dorsal intercalation is essential for successful elongation of the embryo at later stages, although it is not required for ventral enclosure or dorsal cell fusions (Heid et al., 2001). The alignment of cells causes a slight lengthening of the dorsal hypodermis relative to the lateral and ventral sides that causes a slight ventral bend in the body.

As dorsal intercalation nears completion, ventral enclosure begins (HypFIG 3). The enclosure of the ventral surface of the embryo involves a three-step process that leads to wrapping of the embryo in an epithelial monolayer (HypFIG 4A&B). In the initial step, two pairs of âleading cellsâ from the dorsolateral side elongate toward the ventral midline by extending actin-rich filopodia between the neuronal precursor cells underneath them. As these cells meet at the midline, the anterior pair of the leading cells is the first to establish stable adherens junctions, and eventually they fuse after enclosure to form part of the hyp 6 syncytium. The posterior pair also fuses and forms part of the hyp 7 syncytium. As the leading cells move toward the midline, the second step is initiated by the hypodermal cells that are posterior to the leading cells (the ventral pocket cells). These cells become wedge shaped and elongate toward the midline to form a âventral pocketâ around the ventral midline. In the third step, this pocket is sealed, possibly by an actomyosin-dependent purse-string mechanism or by migration of its free edges (Williams-Masson et al., 1997; Simske and Hardin, 2001). If the proper organization of the substrate for migration of hypodermal cells does not occur during earlier stages of embryogenesis, ventral enclosure defects arise. One example of this is a failure in gastrulation cleft closure (George et al., 1998; Chin-Sang et al., 1999; Chin-Sang and Chisholm, 2000).

After the ventral enclosure is completed, around 300-350 minutes after first cell cleavage at 20Â°C, the embryo begins to elongate along its anterior-posterior axis (Priess and Hirsh, 1986; Simske and Hardin, 2001; Chisholm and Hardin, 2005). Apical surfaces of the hypodermal cells are squeezed circumferentially, resulting in pressure on internal structures and elongation of the whole embryo. Elongation causes the circumference of the animal to decrease threefold and its length to increase about fourfold (HypFIG 4C). As a result, the embryo changes from a lima-bean-like shape to a long, thin tube at threefold stage (see IntroFIG7). At the beginning of elongation, circumferential actin and tubulin filament bundles form in all hypodermal cells and are associated with the apical membranes. Actin filaments are anchored to adherens junctions at lateral cell margins via cadherin-catenin complexes. As elongation proceeds, actin filaments in the seam cells shorten (Costa et al., 1997; Costa et al., 1998; Priess and Hirsh, 1986). It has been suggested that the lateral hypodermal cells (seam cells) actively drive hypodermal elongation and that the contractile force that they generate is transmitted to the rest of the hypodermis via adherens junctions (Ding et al., 2004). Elongation proceeds at about 50 Î¼m/hr and is completed at around 600 minutes. The circumferential actin bundles disappear after elongation is complete (Priess and Hirsh, 1986; Costa et al., 1997). The integrity of the hypodermal sheet is essential for successful elongation; it is reinforced by the embryonic sheath, which is secreted over the surface of the embryo before elongation, and by microtubule bundles in dorsal and ventral hypodermal cells (Priess and Hirsh, 1986; Ding et al., 2004). These circumferentially organized microtubules probably distribute the force generated by actomyosin contraction. Intact muscle structure and attachments (fibrous organelles) that link muscle and hypodermis are required for continuation of the process in later stages of elongation. Mutants that show complete absence of muscle function fail to elongate beyond the twofold stage. Once elongation is completed, the embryo secretes a cuticle that maintains the body shape and replaces the embryonic sheath.

The hypodermal syncytia are formed by secondary cell fusions in the embryo, most of which take place as the embryos elongate (Podbilewicz and White, 1994; Podbilewicz, 2000, 2006). These cell fusions generally follow an order, although it can vary (Mohler et al., 1998). Fusion between cells takes place by two sequential processes; initial formation of a pore and expansion of the opening by internalization of the fusing cell membranes (Mohler et al., 1998). As the embryo is enclosed ventrally, about 340 minutes after first cleavage (before comma stage), the first cell-to-cell fusion occurs between two anterior ventral cells to initiate formation of hyp 7 syncytium (HypTABLE 2) (Podbilewicz and White, 1994). Fusion events then progress towards the posterior part of the elongating embryo, followed by fusion of the dorsal and ventral syncytia (Singh and Sulston , 1978; Priess and Hirsh, 1986; Hedgecock et al., 1987). Thus, at hatching, a total of 23 cells have joined to make the hyp 7 syncytium that covers most of the dorsal surface and parts of the ventral surface of the head and the tail (HypFIG 5). The anterior ring of hyp 7 covers the area around the excretory canal, and another posterior ring covers the post-anal region. Between these two rings, hyp 7 syncytium is not cylindrical at this time because of the presence of a lateral row of seam cells and a ventral row of P cells on each side (HypFIG 5A). The hyp 6 syncytium is initially formed by two separate fusions that then join to make the annular hyp 6 during elongation phase of embryogenesis. At this time, hyp 6 is connected to hyp 5 and hyp 7 by adherens junctions (HypFIG 5D) (Sulston et al., 1983; Podbilewicz and White, 1994; Shemer and Podbilewicz, 2000). At the end of embryogenesis the hyp 6 ring contains four dorsal and two ventral nuclei, while the hyp 7 ring contains six ventral, two dorsal and fifteen dorsolateral nuclei (HypFig 5A). The hyp 5 syncytium forms after the left and right lateral hyp 5 cells migrate and fuse. The left and right ventral hyp 4 cells fuse to initiate formation of the hyp 4 syncytium. The two cells that make the hyp 10 syncytium in the tail fuse between 1.5-fold and threefold stages.

  3) Post-embryonic Development of the Hypodermis

During larval development, the body of the animal grows significantly, without many changes in the ectodermal body plan. The hyp 7 syncytium, which covers most of the body, must increase in volume accordingly. The seam cells must also grow to adapt to the increasing body size. To accommodate this growth, an additional 116 cells are added to hyp 7 during postembryonic development from P- and seam-cell lineages and from hyp 6 (HypFIG 1B&C). The seam cells, excluding H0, undergo a stem-cell division at the beginning of each larval stage and contribute additional 98 nuclei to the hyp 7 syncytium (HypFIG 6, 7 & 8 ). Soon after they are born, the daughters of seam stem cells that will become part of hyp 7 endoreduplicate their DNA and become tetraploid (Hedgecock and White, 1985). In contrast, the embryonically derived hyp 7 nuclei remain diploid.

At hatching, the 12 unfused ventral hypodermal cells (P1-P12) are positioned as two parallel rows, with each cell confronting its bilateral homolog along the ventral midline (HypFIG 5C&D). In L1, these cells interdigitate to form a single row of cells on the ventral side (HypFIG 9) (Sulston and Horvitz, 1977). P1-P12 ventral cells divide soon after this, and the anterior daughters detach from the epithelium and become neuroblasts (Sulston and Horvitz, 1977; Hedgecock et al, 1987). The posterior daughters of P1, P2 and P9-12 fuse with hyp 7 at the end of the L1 stage, whereas the posterior daughters of P3-P8 divide at the L3 stage to make 12 cells. Of these, the daughters of P3p, P4p, and  P8p fuse with hyp 7; the daughters of P5p, P6p and P7p become vulva precursor cells (HypFIG 1C).



  4) Adult Hypodermis

In adult C. elegans, the hypodermis is composed of the main body syncytium, hyp 7 and smaller hypodermal cells in the head and  the tail, numbered from hyp 1 to hyp 5 and hyp 8 to hyp 11 (also, hyp 13 in the male). In the adult, hyp 7 contains 139 nuclei and envelops the whole body, except for the extreme head and tail. The hypodermal cells of the head and tail are generated during embryogenesis and acquire no additional nuclei post-embryonically.

The lips anterior to the buccal cavity are covered by three narrow, concentric rings of hypodermal cells (hyp 1, hyp 2 and hyp 3), which serve to unite the outer hypodermis to the epithelial lining of the digestive tract (HypFIG 10 and HypFIG 11, InterFIG 1). hyp 1 forms the innermost ring encircling the tip of the lips and connects to the arcade cells of the buccal cavity. hyp 3 forms the outermost ring and connects to hyp 2 on the inside and hyp 4 on the outside. All five hypodermal cells of the anterior head are syncytial, containing two to three nuclei (HypTABLE 1). Because of their posterior translocation during embryogenesis, the structures of these cells are similar to the arcade cells, such that their cell bodies are situated posterior to the concentric rings and connected to them by thin cytoplasmic processes (InterFIG 2).

The four tail tip hypodermal cells, hyp 8-11, are generated in early embryogenesis. During the elongation phase, they acquire their characteristic tapered shapes. This tapered shape continues throughout all stages of the hermaphrodite; it transforms into a complex fan-like shape in mid-L4 stage in males (Nguyen et al., 1999). hyp 8-10 closely fit onto one another in a succeeding fashion to make up the anal hypodermal ridge, which stretches between the dorsorectal ganglion and tail tip (HypFIG 12). hyp 11 lies just above the anal hypodermal ridge, separated from it by a basal lamina. The nuclei of hyp 8-10 lie within the ridge towards the anterior of each cell, whereas the nucleus of hyp 11 is located asymmetrically on the dorsal left side. Adherens and gap junctions link the neighboring hypodermal cells of the tail (see also Gap Junctions). The neuronal processes that extend to the extreme tail tip either penetrate through (PVR, PDB, PHC) the hypodermal cells or run next to them (PLM, PLN, PVR, PHC), sharing a basal lamina (Nguyen et al., 1999). Behind the phasmid openings, this basal lamina eventually ends, and the extreme tail whip consists of closely packed hypodermal (hyp 9 and hyp 10) and neuronal processes (Nguyen et al., 1999).

  5) List of Hypodermal Cells

hyp 7 (LL40) - V5L.ppppp

hyp 7 (LL45) - V6L.ppa

hyp 7 (LL46) - V6L.ppppa

hyp 7 (LL47) - TL.aa

hyp 7 (LL48) - TL.apaa

hyp 7 (LL49) - TL.apap

hyp 7 (LR18) - V2R.pappa

hyp 7 (LR19) - V2R.ppa

hyp 7 (LR20) - V2R.pppa

hyp 7 (LR21) - V2R.ppppa

hyp 7 (LR22) - V3R.a

hyp 7 (LR23) - V3R.paa

hyp 7 (LR24) - V3R.papa

hyp 7 (LR25) - V3R.pappa

hyp 7 (LR26) - V3R.ppa

hyp 7 (LR27) - V3R.pppa

hyp 7 (LR28) - V3R.ppppa

hyp 7 (LR29) - V4R.a

hyp 7 (LR30) - V4R.paa

hyp 7 (LR31) - V4R.papa

hyp 7 (LR32) - V4R.pappa

hyp 7 (LR33) - V4R.ppa

hyp 7 (LR34) - V4R.pppa

hyp 7 (LR35) - V4R.ppppa

hyp 7 (LR36) - V5R.a

hyp 7 (LR37) - V5R.ppa

hyp 7 (LR38) - V5R.pppa

hyp 7 (LR39) - V5R.ppppa

hyp 7 (LR40) - V5R.ppppp

hyp 7 (LR41) - V6R.a

hyp 7 (LR42) - V6R.paa

hyp 7 (LR43) - V6R.papa

hyp 7 (LR44) - V6R.pappa

hyp 7 (LR45) - V6R.ppa

hyp 7 (LR46)- V6R.ppppa

hyp 7 (LR47) - TR.aa

hyp 7 (LR48) - TR.apaa

hyp 7 (LR49) - TR.apap

3. Tail (posterior to anus; all embryonic)

hyp 7 (V22/23) - ABplappppa (aka hyp 13)

hyp 7 (V22/23) - ABprappppa (aka hyp 13)

hyp 8/9 - ABplpppapap

hyp 8/9 - ABprpppapap

hyp 10 (V1/2) - ABplppppppp

hyp 10 (V1/2) - ABprppppppp

hyp 11 - Cpappv

Entire hyp7 syncytium

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