All tissues in the human body are encased with a thin, dense, web of proteins called the basement membrane. These membranes separate and help shape tissues, while protecting them from mechanical damage such as stretching. However, despite serving as important barriers, basement membranes must be rapidly removed at specific times and places to allow tissues to grow and change shape. This process also permits cells to enter and leave tissues, such as immune cells when they search for disease-producing agents. This creates a paradox: how does a tissue create a tough, impassable barrier that can also be rapidly removed at specific times and places?

Recent research has shown that basement membranes can slide over a tissue, and thus rapidly move the barriers to create openings for tissue growth and reshaping. However, it was not known how the cells within tissues that are normally firmly attached to basement membrane control when and where basement membrane can slide.

Now, McClatchey, Wang et al. have carefully observed the tissues and basement membranes in a small worm called Caenorhabditis elegans under a microscope. This revealed that a single cell, called the anchor cell, relays a signal that instructs a group of neighboring cells to let go of the basement membrane at a specific time to allow tissue reshaping. Further experiments revealed that this signal causes cells to reduce the amount of a protein named dystroglycan at their surface.

Dystroglycan is present in most tissues and helps stick the cells of tissues to basement membranes. The loss of dystroglycan was previously reported to promote the spread of cancer, although its role in cancer progression was not clear. The findings of McClatchey, Wang et al. now suggest that tumors that lose dystroglycan might allow the basement membranes surrounding them to slide, creating openings that allow the cancers to spread.

Finally, McClatchey, Wang et al. also found that a protein named CTG-1, one of a family of proteins thought to regulate the movement of proteins within cells, restricts the levels of dystroglycan at cell surface. As such, the next challenge will be to understand exactly how CTG-1 limits the amount of dystroglycan at the cell surface.

The basement membrane (BM) is a cell-associated, dense, sheet-like form of extracellular matrix that underlies all epithelia and endothelial tissue, and surrounds muscle, fat, and Schwann cells (Halfter et al., 2015; Yurchenco, 2011). BMs are built on polymeric laminin and type IV collagen networks that arose at the time of animal multicellularity, and may have been required for the evolution of complex tissues (Hynes, 2012; Ozbek et al., 2010). Consistent with this idea, BMs provide tissues with mechanical support, barrier functions, and cues for polarization, differentiation and growth (Breitkreutz et al., 2013; Hay, 1981; Poschl et al., 2004; Rasmussen et al., 2012; Suh and Miner, 2013; Yurchenco, 2011).

Although it was generally thought that cell-BM interactions are static, live imaging studies have revealed that cell-BM interfaces are highly dynamic (Morrissey and Sherwood, 2015). One of the most dramatic examples of this mobility is cell-BM sliding, during which epithelial cell layers and their underlying BM sheets move (slide) along one another independently to regulate tissue remodeling or renewal. Examples of cell-BM sliding are varied and include egg chamber rotation in Drosophila, where the follicle cells move along BM and deposit constricting strips of aligned type IV collagen, which direct egg elongation along the anterior-posterior axis (Cetera and Horne-Badovinac, 2015; Haigo and Bilder, 2011). During salivary gland growth in vertebrates, the BM slides away from the bud tip toward the duct, allowing bud expansion while restricting growth at the duct (Harunaga et al., 2014). Further, BM labeling and pulse chase experiments revealed that intestinal epithelial cells derived from the stem cell crypt slide along the BM towards the villus tips during differentiation to rapidly renew the gut epithelium (Clevers, 2013; Trier et al., 1990). Cell-BM sliding may be a common morphogenetic process that regulates organ shaping during development, tissue homeostasis, and diseases such as cancer, where remodeling of cell-BM interfaces frequently occur (Kelley et al., 2014; Rowe and Weiss, 2008). Because of the challenge of visualizing and experimentally examining dynamic cell-BM interactions in vivo, however, mechanisms controlling cell-BM sliding remain largely unknown.

An experimentally tractable model to examine cell-BM sliding during tissue remodeling is uterine-vulval attachment in C. elegans (Schindler and Sherwood, 2013), a developmental process that is necessary for effective mating and egg laying in the worm. During the mid-L3 larval stage, the uterine-vulval connection is initiated by a specialized uterine cell, the anchor cell (AC), that breaches the BM that separate these tissues and attaches to the underlying vulval cells. Following AC invasion, the gap in the BM widens further, which allows additional connection between uterine and vulval cells (Ihara et al., 2011). BM gap widening does not involve BM degradation. Instead, optical highlighting of BM and manipulation of tissue dynamics has shown that growth and morphogenesis of the uterine and vulval tissues generate forces on the BM that drive BM sliding over the vulval and uterine cells to further expand the gap (Ihara et al., 2011). The vulval cells have a key role in controlling the extent of BM movement. The centrally located vulval E and F cells, which contact the BM gap boundary, undergo precisely timed divisions to initiate BM sliding--cell rounding during divisions dramatically reduces cell contact with the BM and allows the BM to slide over the vulE and F cells (Matus et al., 2014). The BM stops sliding on the non-dividing vulD cell, which concentrates the BM adhesion receptor INA-1/PAT-3 (integrin) to stabilize the BM gap boundary (Ihara et al., 2011; Matus et al., 2014). While vulval cell divisions control BM sliding on the vulval side of the uterine-vulval connection, the role of the uterine π cells, which flank the AC, and sit on the opposing side of the BM gap boundary, remain unclear.

Many receptors bind BM components and are possible regulators of BM sliding. Two of the most prominent classes of adhesion receptors that link BM to the cytoskeleton are integrin family members and the receptor dystroglycan (Bello et al., 2015; Kramer, 2005; Yurchenco, 2011). Most studies have focused on how these receptors are activated or upregulated to strengthen adhesion; however there is a growing appreciation of the importance of integrin and dystroglycan downregulation in morphogenetic, homeostatic, and disease processes (Agrawal et al., 2006; Bouvard et al., 2013; Miller et al., 2015; Nakaya et al., 2013). Cells utilize a variety of mechanisms to reduce BM receptor adhesion. These include transcriptional downregulation, production of negative regulators that interfere with receptor activation, alterations in phosphorylation status, and changes in localization and trafficking (Bouvard et al., 2013; Nakaya et al., 2013; Poulton and Deng, 2006). Whether these strategies are used to modulate adhesion to control BM sliding is unknown.

To address how the uterine BM gap boundary cells control BM sliding during uterine-vulval attachment in C. elegans, we carried out a mutagenesis screen. Through this screen we identified a putative null mutant in the gene encoding the LIN-29 protein, which is a Kruppel-family EGR (early growth response) protein (Harris and Horvitz, 2011), that is deficient in BM sliding. We show that LIN-29 is expressed and functions in the invading AC to promote BM sliding. We further find that LIN-29 regulates BM sliding through its role in maintaining AC expression of LAG-2, a transmembrane Notch ligand, which activates Notch signaling in the neighboring BM gap boundary cells, the uterine π cells that sit on BM next to the nascent breach. Through a targeted uterine-specific RNAi screen of putative direct Notch targets, we find that Notch activation in these uterine cells upregulates ctg-1 expression, which encodes a Sec14-GOLD domain phosphatidylinositol transfer protein that belongs to a class of proteins implicated in regulating vesicle trafficking (Grabon et al., 2015). Finally, using photobleaching, CRISPR/Cas-9 targeted knockout, and cell-specific rescue experiments, we demonstrate that CTG-1 functions in the uterine π cells to limit the cell surface trafficking of DGN-1 (dystroglycan), and that reduction of DGN-1 is sufficient to promote BM sliding. Together these studies identify a new morphogenetic pathway—from signaling mechanism to effector—that promotes BM sliding, which can be used by invasive cells to enlarge BM openings and allow the direct interaction of cells between tissues.

The shifting of cell-BM interfaces is crucial in many diverse morphogenetic events, including intestinal epithelial renewal, branching morphogenesis, and BM deposition (Clevers, 2013; Glentis et al., 2014; Morrissey and Sherwood, 2015). How BM sliding is controlled, however, remains poorly understood. We show here that the AC in C. elegans further widens a breach it creates in BM during uterine-vulval attachment by promoting BM sliding in neighboring uterine cells. LIN-29 maintains the expression of the Notch ligand LAG-2 in the AC, which leads to the activation of Notch signaling and induction of uterine π cell fate in the neighboring cells that sit over the nascent BM gap boundary. Notch activation in turn leads to upregulation of the Sec14 family phospholipid transfer protein CTG-1 in these BM gap boundary cells, which restricts trafficking of the receptor DGN-1 (dystroglycan) to the cell-BM interace. Our data suggest that the proper regulation of DGN-1 trafficking modulates cell-BM adhesion and allows the BM slide, which further widens the BM breach. This work reveals a new morphogenetic signaling pathway that promotes cell-BM sliding (See Summary Figure 9).

Figure 9

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During cell-BM sliding, the cells, the BM, or both shift position in relationship to each other. During uterine-vulval attachment in C. elegans, the linked ventral and gonadal BMs slide over vulval and uterine cells to expand the BM gap, and the vulval cells also appear to move (through migration and invagination) inside the gap to form direct contacts with uterine cells (Ihara et al., 2011; Schindler and Sherwood, 2013). It has previously been shown that vulval cell divisions at the BM gap boundary controls BM sliding (Matus et al., 2014). During vulval invagination and growth, the centrally located vulE and F cells divide and reduce their contact with the BM during cell rounding, allowing the BM to slide over these cells. The BM ultimately ceases sliding and the BM gap boundary stabilizes on the non-dividing vulD cell. Blocking the divisions of vulE and F halts BM sliding prematurely resulting in a narrower BM gap, while inducing vulD divisions causes the BM to slide further and enlarges the opening (Matus et al., 2014). Here we have found that uterine cells at the BM gap boundary regulate BM movement through a distinct mechanism independent of cell division. Uterine π cell divisions are not coordinated with vulval cell divisions during BM movement. Further, blocking uterine π cell divisions did not halt BM sliding. Instead, through a forward genetic screen, site of action, and expression studies, our data indicate that the invading AC directs a morphogenetic signaling program that promotes BM sliding in neighboring uterine cells: (1) the AC expresses the transcription factor LIN-29, (2) LIN-29 activates Notch signaling and induction of the π cell fate in neighboring uterine cells (Newman et al., 2000), (3) as a part of π cell fate induction, Notch activation upregulates ctg-1, which restricts trafficking of the BM adhesion receptor DGN-1 (dystroglycan) to the cell-BM interface and allows BM sliding. Together, these observations suggest that after AC invasion, the uterine π cells loosen BM adhesion, allowing the BM to slide along the π cells to a precise site determined by the dividing vulE and F cells and non-dividing vulD. This model is supported by the observed flexibility of BM boundary position, which can be adjusted by manipulating vulval cell divisions. The distinct, but temporally coordinated, mechanisms controlling BM movement in the uterine and vulval cells precisely position the BM gap boundary to ensure robust uterine-vulval attachment.

Very few examples of gene regulatory networks guiding morphogenetic cellular behaviors leading to cell fate specification are known (Christiaen et al., 2008). Using a focused RNAi screen we found that ctg-1, which encodes a Sec14 family phosphatidylinositol-transfer protein (PITP) (Tripathi et al., 2014), is a crucial target of Notch signaling during π cell fate specification that promotes BM sliding. Consistent with ctg-1 being a direct transcriptional target of Notch, the ctg-1 upstream regulatory region contains 19 predicted binding sites for the Notch transcriptional activator LAG-1 (Suppressor of Hairless) (Yoo, 2004). Furthermore, ctg-1 expression is upregulated in the π cells at the time of activated LIN-12 (Notch) signaling, and its expression is dependent on LIN-29-directed Notch signaling. In addition, uterine-cell specific RNAi and genetic loss of ctg-1 reduced BM sliding, which phenocopies loss of Notch signaling in these cells. Sec14 family PITPs are unlikely to be true carriers of phospholipids. Instead, studies suggest that Sec14 family PITPs function as scaffolds or nanoreactors that present phosphatidylinositol to phosphatidylinositol-4 kinase (PI4K) to regulate specific protein and membrane trafficking pathways in the trans-Golgi and endosomal recycling system (Cockcroft and Garner, 2011; Curwin, 2013; Curwin et al., 2009; Mousley et al., 2008; Schaaf et al., 2008; Tripathi et al., 2014). Consistent with this notion, our work also indicates that the C. elegans PI4K, pifk-1, is required in the uterine cells to promote BM sliding.

The Sec14 family has expanded significantly in multicellular eukaryotes. Whereas yeast have six Sec14 family members, we found C. elegans has at least 16 and vertebrates have at least 20 (Bankaitis et al., 2010). Little, however, is known about the cellular process controlled by many these proteins (Grabon et al., 2015). Our work suggests that CTG-1 regulates the trafficking of DGN-1(dystroglycan) to the cell surface and promotes de-adhesion from BM to control BM sliding. Notably, localization and photobleaching studies indicate that the integrin heterodimer INA-1/PAT-3, another key BM receptor, was unaffected by loss of ctg-1, suggesting that CTG-1 function is highly specific. Loss of LIN-29-mediated Notch signaling (and thus ctg-1 expression in the uterine cells) led to an increase of DGN-1 on the surface of uterine cells, but did not alter dgn-1 gene expression. Photobleaching experiments in wild type and lin-29 mutants (lack upregulation of ctg-1) indicated that ctg-1 expression in the π cells restricts the rate of DGN-1 trafficking to the cell-BM interface. Interestingly, in CTG-1 the Sec14 domain is paired with a GOLD (Golgi Dynamics) domain, which, though its function has yet to be completely characterized, may regulate the selection of proteins being trafficked from the Golgi, thus affecting their secretion to the plasma membrane or routing to the endosome-lysosomal system (Anantharaman and Aravind, 2002; Schimmoller et al., 1995). These results suggest that CTG-1 might reduce cell-BM adhesion by regulating a vesicular pathway with specificity for DGN-1, possibly slowing DGN-1 delivery to the cell surface or directing it to the endosome-lysosome system. The function of Sec14-GOLD proteins is poorly understood, and CTG-1 does not show strong localization to any specific domain in the uterine π cells. Thus, we cannot rule out possible functions for CTG-1 in mediating increased removal of DGN-1 from the cell surface or slowing lateral plasma membrane trafficking to restrict DGN-1 at the cell-BM interface. While the specific mechanism by which CTG-1 restricts DGN-1 trafficking remains unclear, we found that reduction of DGN-1 restored BM sliding in the absence of ctg-1, strongly supporting the functional significance of reduced localization and trafficking of DGN-1.

The two most prominent BM receptors that transduce signals and link the cells’ cytoskeleton to the BM are integrin heterodimers and dystroglycan (Bello et al., 2015; Yurchenco, 2011). Unlike mammals, which construct 24 known αβ integrin heterodimers, C. elegans make only two, and only one of these, αINA-1/βPAT-3, is expressed with DGN-1 (dystroglycan) in the uterine π cells (Hagedorn et al., 2009; Ihara et al., 2011). Integrin and dystroglycan are co-expressed widely, and likely have many distinct roles, such as having opposing effects on extracellular-regulated kinase (ERK) activation (Ferletta et al., 2003). However, how these proteins interact and coordinate functions in regulating cell-BM communication and adhesion has been challenging to elucidate as a result of tissue complexity and the large family of integrin heterodimers in vertebrates (Bello et al., 2015; Nakaya et al., 2013). Interestingly, our data suggest that INA-1/PAT-3 is not downregulated to promote BM sliding in the uterine π cells. Further, unlike loss of dgn-1, uterine-specific loss of ina-1 did not rescue BM sliding in the lin-29 mutant background. Our results indicate that DGN-1 is the primary BM adhesion receptor that controls cell-BM sliding in the uterine π cells, while integrin appears to have a function(s) independent of BM sliding in these cells. These results suggest that different BM receptors may allow cells to have diverse and concurrent signaling and adhesive interactions with BM.

While dystroglycan has been most extensively studied in its association with the dystrophin complex and muscular dystrophies, it is broadly expressed and implicated in regulating many cellular processes, including BM assembly, cell migration, axon outgrowth, retinal layering, and Schwann cell wrapping (Bello et al., 2015; Moore and Winder, 2010). Notably, dystroglycan is also required for branching morphogenesis in glandular epithelium, a process that is thought to require BM sliding (Durbeej et al., 2001; Harunaga et al., 2014). Further, it has been shown that loss of basally localized dystroglycan during chick gastrulation promotes breakdown of BMs during the epithelial-to-mesenchymal transition that forms mesoderm (Nakaya et al., 2011). Thus, dystroglycan may have a fundamental role in mediating BM remodeling events during development. Importantly, loss or reduction of dystroglycan is also emerging as a common event in the progression of epithelial derived cancers, including breast, prostate, colon, cervical, and renal adenocarcinomas (Cross et al., 2008; Esser et al., 2013; Sgambato et al., 2007, 2003, 2006). As regulated loss or reduction of dystroglycan during development creates and widens BM gaps through BM loss and sliding, uncontrolled loss of dystroglyan during cancer progression may lead to the breakdown of BM barriers to facilitate tumor spread. Thus, understanding mechanisms that control dystroglycan levels at the cell surface are not only important in understanding tissue morphogenesis, but may provide new strategies to halt cancer progression.

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Author details

1. Shelly TH McClatchey

   Department of Biology, Duke University, Durham, United States

   Contribution

   STHM, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Zheng Wang

   Competing interests

   The authors declare that no competing interests exist.

2. Zheng Wang

   1. Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Wuhan, China
   2. Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
   3. Department of Gastrointestinal Surgery, Union Hospital, Wuhan, China
   4. Development and Molecular Oncology Laboratory, Union Hospital, Wuhan, China

   Contribution

   ZW, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Shelly TH McClatchey

   Competing interests

   The authors declare that no competing interests exist.

3. Lara M Linden

   Department of Biology, Duke University, Durham, United States

   Contribution

   LML, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

4. Eric L Hastie

   Department of Biology, Duke University, Durham, United States

   Contribution

   ELH, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

5. Lin Wang

   1. Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Wuhan, China
   2. Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

   Contribution

   LW, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Wanqing Shen

   1. Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Wuhan, China
   2. Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

   Contribution

   WS, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Alan Chen

   Department of Biology, Duke University, Durham, United States

   Contribution

   AC, Conception and design, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

8. Qiuyi Chi

   Department of Biology, Duke University, Durham, United States

   Contribution

   QC, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

9. David R Sherwood

   Department of Biology, Duke University, Durham, United States

   Contribution

   DRS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   david.sherwood@duke.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-2245-2334

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