Extracellular matrix dynamics and functions in the social amoeba Dictyostelium: A critical review

Biochimica et Biophysica Acta 1861 (2017) 2971–2980

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Review

Extracellular matrix dynamics and functions in the social amoeba Dictyostelium: A critical review Robert J. Huber a,⁎, Danton H. O'Day b,c a b c

Department of Biology, Trent University, Peterborough, Ontario, Canada Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada Department of Biology, University of Toronto Mississauga, Mississauga, Ontario, Canada

a r t i c l e

i n f o

Article history: Received 8 July 2016 Received in revised form 19 September 2016 Accepted 26 September 2016 Available online 28 September 2016 Keywords: Dictyostelium discoideum Extracellular matrix Development Matricellular EGF-like repeats Cell motility

a b s t r a c t Background: The extracellular matrix (ECM) is a dynamic complex of glycoproteins, proteoglycans, carbohydrates, and collagen that serves as an interface between mammalian cells and their extracellular environment. Essential for normal cellular homeostasis, physiology, and events that occur during development, it is also a key functionary in a number of human diseases including cancer. The social amoeba Dictyostelium discoideum secretes an ECM during multicellular development that regulates multicellularity, cell motility, cell differentiation, and morphogenesis, and provides structural support and protective layers to the resulting differentiated cell types. Proteolytic processing within the Dictyostelium ECM leads to specific bioactive factors that regulate cell motility and differentiation. Scope of review: Here we review the structure and functions of the Dictyostelium ECM and its role in regulating multicellular development. The questions and challenges that remain and how they can be answered are also discussed. Major conclusions: The Dictyostelium ECM shares many of the features of mammalian and plant ECM, and thus presents an excellent system for studying the structure and function of the ECM. General significance: As a genetically tractable model organism, Dictyostelium offers the potential to further elucidate ECM functions, and to possibly reveal previously unknown roles for the ECM. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Comprised primarily of glycoproteins, proteoglycans, carbohydrates, and collagen, the extracellular matrix (ECM) of mammalian cells is more than just the sum of its parts [1]. It is the dynamic interface between the cell and its extracellular environment. As such, it plays a true intermediary role not only in protecting the cell that it surrounds, but also in directing cellular processes in response to environmental Abbreviations: AcbA, acyl-CoA binding protein; AD, Alzheimer's disease; ALC, anteriorlike cell; cAMP, cyclic adenosine monophosphate; CaBP, calcium-binding protein; Cad, calcium-dependent cell adhesion molecule; CaM, calmodulin; CaMBD, calmodulinbinding domain; CaMBP, calmodulin-binding protein; CV, contractile vacuole; DIF, differentiation-inducing factor; ECM, extracellular matrix; EGF, epidermal growth factor; EGFL, epidermal growth factor-like; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; GRASP, Golgi reassembly stacking protein; HD, Huntington's disease; PD, Parkinson's disease; Psa, puromycin-sensitive aminopeptidase; Psi, presporeinducing factor; Pst, prestalk; SPARC, secreted protein acidic and rich in cysteine; SDF, spore differentiation factor; Sib, similar to integrin beta; Tenascin C, tenascin cytotactin; Tgr, transmembrane, IPT, IG, E-set, repeat; TipD, autophagy protein 16; TSP, thrombospondin; vWF, von Willebrand factor. ⁎ Corresponding author at: Trent University, Department of Biology, 2140 East Bank Drive, Peterborough, Ontario K9J 7B8, Canada. E-mail address: [email protected] (R.J. Huber).

http://dx.doi.org/10.1016/j.bbagen.2016.09.026 0304-4165/© 2016 Elsevier B.V. All rights reserved.

cues. The mammalian matrisome constitutes greater than 1% of the proteome, and the vast diversity of functions of the ECM and their mode of action are increasingly becoming clear [2]. As a mediator of cellular behaviour, development, and physiology, the mammalian ECM plays central roles in the regulation of cell motility, proliferation, shape, signalling, and survival, with new roles such as mechanochemical function coming to light [2]. The ECM is not just a physical sieve that molecules must make their way through. It is also a dynamic functionary that can trap, modify, or destroy those molecules. At times, the ECM can also malfunction by processing proteins in a way that is harmful [1,3]. Once considered to be primarily a structural element of metazoans, it should be recognized that even the cell walls of single bacteria, plant cells, and spores are forms of ECM. Organisms with less complex design and comparatively simpler lifestyles could be useful in analyzing the functions of the ECM. One such organism is the social amoebozoan Dictyostelium discoideum. Dictyostelium is a nucleated social microbe that feeds and grows as single cells. When prompted by starvation, it undergoes chemotactic aggregation to form a multicellular tissue called a pseudoplasmodium or slug. Differentiation of cells within the slug ultimately gives rise to a fruiting body consisting of a stalk supporting a droplet of spores [4]. During this transition to multicellularity, a true

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dynamic ECM is produced that plays a central role in the transition of this tissue into a fruiting body. Many of the events that are mediated by the Dictyostelium ECM are the same as those seen in mammals—in fact, many more than were previously thought. Here we address them.

2. Extracellular matrices of social amoebozoans As Dictyostelium cells initiate multicellular development, an event triggered by the diminishment of their microbial food supply, they begin to secrete an ECM called a slime sheath. ECM deposition becomes evident during cyclic AMP (cAMP)-mediated aggregation where cells at the center of the aggregate begin to secrete a complex ECM composed of cellulose, polysaccharide, protein, and glycoconjugates [5–8]. In other amoebozoan species such as Polysphondylium pallidum, the ECM surrounding both the central aggregate and incoming streams of cells is incredibly strong, so much so that both structures can be lifted off as a group from an agar surface [9]. Once aggregation is complete, the resulting multicellular pseudoplasmodium or slug continues to secrete ECM material from its tip, which is the site of cAMP synthesis and stalk cell formation [10,11]. The secreted material forms a sheath around the slug as the cells within begin the first stages of differentiation (Fig. 1). The ECM functions as a physical barrier, preventing the loss or entry of new cells into the multicellular aggregate, and may also function as a barrier to diffusion [12–13]. Terminal differentiation of prestalk and prespore cells into stalk cells and spores, respectively, occurs during culmination resulting in the formation of a fruiting body consisting of an unencased droplet of viable spores suspended atop a slender stalk. Cells within the stalk have thick walls and the stalk tube is surrounded by a cellulose-, protein-, and glycoconjugate-containing sheath, which represents another type of ECM in Dictyostelium [14–16]. Following culmination, each spore is surrounded by a rigid extracellular wall referred to as a spore coat, which is composed primarily of

cellulose, protein, and polysaccharide [16,17]. The spore coat protects the spore from environmental conditions and allows it to remain viable for long periods of time [16]. During prespore cell differentiation, cells package all of the material required for spore coat formation, except cellulose, into prespore vesicles, which are then secreted outside the cell into the interspore matrix [16]. Both the spore coat and interspore matrix are additional forms of ECM in Dictyostelium. Cellulose is synthesized across the plasma membrane as differentiating spores rise up the stalk. The secreted components in the interspore matrix interact with the shrunken cell and form a coat around the newly formed spore. A layer of cellulose is sandwiched between a proteinaceous inner layer near the plasma membrane, and an outer protein-rich layer that acts as a permeability barrier towards exogenous macromolecules [16]. The function of the unincorporated material in the matrix is still unclear, however it is reasonable to suggest that this reservoir of ECM material helps to prevent dessication and maintain spore dormancy. In addition to spores and stalk cells, the amoebozoans form other types of ECM including the 2-layered walls of unicellular asexual microcysts, and the tripartite walls of sexual macrocysts [18,19]. These extracellular walls and coats provide structure and as yet unverified functions during cyst dormancy. Clearly the ECM is a product of cell secretion, but just as evident, every protein that is secreted will not end up residing as an integral ECM component. Some secreted proteins will be reabsorbed by endocytotic mechanisms. Others will be lost to the extracellular environment, be broken down by proteases as the work their way through the ECM, or will use their proteolytic activity to modify the ECM. In Dictyostelium, proteomic analyses have revealed proteins that are secreted, present in the macropinocytic pathway, and retained within the sheath ECM [20–22]. In addition, the study of individual proteins has provided insight into proteins that are retained, modified, and excluded from the ECM. Here we review that information with a view towards gaining more insight into the Dictyostelium ECM, and how the proteins contained within regulate cell movement, differentiation, and morphogenesis in this model organism. 3. The extracellular matrix of the Dictyostelium slug

Fig. 1. The ECM surrounding the multicellular slug and the cell types contained within. The sheath ECM, which is synthesized from the tip of the multicellular slug, is shed from the back of the slug as it migrates along the substratum. (Top panel) a diversity of processes occur in the ECM during slug migration. Cells secrete EcmA and EcmD which provide structure to the ECM. Secreted proteins such as AcbA and CyrA are processed into bioactive fragments that in turn bind to the cell surface to modulate cellular processes (e.g., spore differentiation and cell motility, respectively). (Bottom panel) different cell types within the slug sort to specific locations.

As the Dictyostelium slug migrates along the substratum, the ECM is left behind as a collapsed tube, which has facilitated analyses of the specific components that make up the ECM [5,7,8,10,22,23] (Fig. 1). Based on the lack of detectable β-actin and α-tubulin, as well as several other cell-specific proteins in western blots, the sloughed off ECM contains few cells [6,22]. As further support, compared to cells within the slug, the ECM contains considerably more serine, glycine, alanine, and valine, and considerably less lysine, arginine, glutamic acid, proline, methionine, and phenylalanine [6]. Smith and Williams [6] showed that proteins comprise ~ 50% of the dry weight of the sheath ECM. Recent proteomic profiling of the sheath ECM revealed proteins involved in metabolic processes (~50%), transport (~9%), fruiting body development (~ 7%), biological adhesion (~ 4%), proteolysis (~ 3%), and cell motility (~ 2.5%) [22] (Table 1). In addition, of the over 300 proteins identified, ~ 48% are involved in some sort of binding, while ~ 30% are homologous to known enzymes [22] (Table 1). Together, these findings have provided valuable new insight into the primary functions associated with ECM proteins in Dictyostelium. Several proteins have been well established as ECM components in Dictyostelium including the structural proteins EcmA and EcmD, as well as discoidins I and II that are involved in cell adhesion [24–27] (Fig. 1). As anticipated, all of these proteins were detected in a proteomic analysis of the sheath ECM [22]. EcmA has a signal sequence and is composed of 66 CTDC domains (Pfam accession number: PF00526) (www.dictybase.org) (Fig. 2). CTDC domains are ~ 25 amino acid cysteine-rich domains that are unique to Dictyostelium and are found in a large number of Dictyostelium ECM proteins [28]. Proteins that harbor these domains usually have multiple copies. EcmD contains a

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4. Matricellular proteins within the extracellular matrix

Table 1 Functions associated with proteins detected in the Dictyostelium sheath ECM. Functions of sheath ECM proteins Strain

Strain

Biological process

NC4 WS380B Molecular function

NC4 WS380B

Biological adhesion Cell communication Cell cycle Cell differentiation

2.5 4.4 3.3 1.6

4.9 4.2 4.9 1.3

46.3 13.4 0.3 2.7

50.2 9.8 0.3 3.3

Cell division Cell growth

3.3 0.5

4.6 0.7

1.1 3.0

1.3 2.0

Cell morphogenesis Cell motility Chemotaxis to cAMP Culmination during sorocarp development ECM organization

1.4 2.7 0.8 1.6

1.6 2.3 1.0 1.3

1.1 1.1 14.2 1.4

0.3 1.3 14.3 1.6

0.5

0.3

1.1

0.3

Fruiting body development Metabolic process Phototaxis Proteolysis Response to stimulus

6.5

7.2

Polysaccharide binding Protein binding

48.2 0.5 3.5 17.7

51.5 1.0 2.6 19.9

1.4 31.6 1.1 0.3

2.3 28.7 0.7 0.3

Secretion

1.1

2.3

1.9

2.0

Sorocarp morphogenesis Sorocarp stalk development Sporulation resulting in formation of a cellular spore Thermotaxis Transport Unknown

0.3 0.5

1.0 0.3

Vitamin binding Catalytic activity Motor activity Transcription regulator activity Translation regulator activity Transporter activity Unknown

1.4

1.3

Binding ATP binding cAMP binding Calcium ion binding CaM binding Carbohydrate binding Cellulose binding Enzyme binding Ion binding Lipid binding

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12.0 15.6

2.7 2.6 42.8 39.7

0.3 0.3 8.7 9.8 38.7 33.2

GO annotation of proteins detected in the sheath ECM of two wild-type strains of Dictyostelium, NC4 and WS380B. Numbers represent the % of the total number of proteins detected. For a complete list of the proteins identified refer to Fig. S2 in Huber and O′Day [22].

signal sequence and a C-terminal cellulose- and carbohydrate-binding domain (SMART accession number: SM01063) (Fig. 2). Discoidin I and II each contain a discoidin domain as well as a cell attachment site in the N-terminal region of the protein (Fig. 2). Discoidin II also contains a C-terminal lectin-like domain (Fig. 2). Two decades ago, microscopic analyses suggested that the closest underlying cells are tightly adhered to the ECM forming a kind of epithelial tissue [10]. This tissue arrangement may primarily be involved in the maintenance of slug structure, but as discussed below, roles in tissue differentiation and morphogenesis are also possible. To date, the adhesion proteins that mediate this cell-ECM linkage remain to be identified. In addition to discoidins I and II, proteomic profiling of the sheath ECM revealed other adhesion proteins including calcium-dependent cell adhesion molecules 1, 2, and 3 (Cad1, Cad2, and Cad3), contact site B protein A (CsbA), and contact site B protein B (CsbB) [22]. Cad1, Cad2, and Cad3 each contain an N-terminal beta/gamma crystallin domain (Pfam accession number: PF08964) and a C-terminal membrane-binding domain (Pfam accession number: PF14564). CsbA and CsbB each contain a cell-cell adhesion domain (Pfam accession number: PF05720) (Fig. 2). Interestingly, the functions of at least one-third of the proteins in the sheath ECM remains unknown [22] (Table 1). One perplexing aspect of the association between the migrating slug cells and the ECM is the relative absence of cellular material when the ECM is sloughed off from the back of the slug. Clearly any cell-ECM adhesion mechanism that exists must be temporary or comparatively loose to allow the ECM to move over the cell mass during slug migration.

Matricellular proteins by their definition contain binding sites for both the ECM (i.e., matri-) and cell surface proteins (i.e., -cellular) [29]. Members of this protein family regulate a diversity of cellular processes and are linked to a number of human diseases, such as cancer and neurodegeneration [29,30]. In mammals, the most well-studied examples of matricellular proteins include tenascin C, thrombospondin 1 and 2 (TSP-1 and TSP-2), and secreted protein acidic and rich in cysteine (SPARC) [31]. The evolutionary history of these proteins has been reviewed [32]. Some of the key features of matricellular proteins are that they associate with extracellular proteases and growth factors, are expressed at high levels during development, do not directly contribute to the organization or physical properties of extracellular structures, and modulate cellular processes by binding to the cell surface and initiating intracellular signal transduction [29]. While matricellular proteins have been implicated in a number of cellular processes, the most well studied function for these proteins is their ability to modulate cell adhesion and migration. Some matricellular proteins such as tenascin C and TSP-1 contain epidermal growth factor (EGF)-like (EGFL) repeats that bind to the cell surface to modulate cell motility [33,34]. Mammalian ECM proteins typically contain repeated elements such as the TSP type 1 domain, the von Willebrand factor (vWF) domain, and the EGFL domain [35–37]. Interestingly, these domains have also been detected in non-metazoan organisms, including Dictyostelium, and are present in a number of sheath ECM proteins [22,38] (Table 2). In fact, the Dictyostelium genome encodes more EGFL repeat-containing proteins than any other sequenced organism, including humans [39]. In Dictyostelium, the cysteine-rich calmodulin (CaM)-binding protein (CaMBP) CyrA is secreted during development and localizes to the ECM [40,41] (Fig. 1). CyrA contains a signal sequence, a putative CaM-binding domain (CaMBD), and four tandem EGFL repeats in its C-term (Fig. 2). It also contains three CTDC domains within its cysteine-rich region (Fig. 2). Interestingly, CyrA shares many of the key features of matricellular proteins in mammals, including the ability of at least one of its EGFL repeats to increase the rate of cell movement, thus making it the first matricellular protein to be identified in a eukaryotic microbe [40–45] (Fig. 1). TgrM1 (transmembrane, IPT, IG, E-set, Repeat M1), which contains a TSP type 1 domain, is also present in the sheath ECM (Table 2). Intriguingly it belongs to a family of proteins whose members play essential roles in kin recognition and aggregation during development [46–48]. Together, these findings have opened up a new avenue of research in Dictyostelium to investigate the nonstructural components of the ECM that modulate cellular processes during multicellular development. 5. Pattern and polarity in the Dictyostelium slug Over a dozen mammalian ECM proteins, as well as their many isoforms, have been shown to regulate morphogenesis, pattern and polarity, and cell and tissue differentiation [49,50]. As the Dictyostelium slug migrates along the substratum, the fate of the future stalk cells and spores is progressively determined, and a pattern and polarity is established in anticipation of culmination [51–53]. Early studies using neutral red staining revealed prestalk cells in the front tip of the slug, a larger population of prespore cells behind them, and a smaller cohort of basal disc cells in the rear of the slug [52,54,55]. Part of this sorting is regulated by cAMP which is secreted by the tip of the slug [55–59]. Closer examination of the gross tri-partite cellular organization revealed more precise details about the cellular patterns within the slug. The prestalk region is sub-divided into the anterior prestalk A (pstA) zone, the posterior prestalk O (pstO) zone, and a cone shaped prestalk A/B (pstA/B) zone within the core of the tip [60,61] (Fig. 1). A prestalk B (pstB) zone is located directly above the substratum within the anterior prespore region [62,63] (Fig. 1). The larger prespore region is comprised

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Fig. 2. Domain architecture of some established ECM proteins in Dictyostelium. UniProt and GenBank Protein were used to identify conserved domains. Domains in each protein are drawn to scale.

of mostly prespore cells, however a number of intermingled anteriorlike cells (ALCs) are also present [64] (Fig. 1). ALCs are similar to the anterior prestalk cells and are thought to function in slug migration and fruiting body formation [63,64]. During culmination, the ALCs sort out from the prespore cells and differentiate to form supportive stalk cell structures [64]. The prestalk U (pstU, not shown as separate ALCs in Fig. 1) cells are a specific subtype of ALCs that are scattered throughout the prespore region however they tend to sort preferentially to the posterior prespore region [65]. During culmination, pstU cells will populate the upper cup of the stalk [65]. Finally, a small cohort of cells that will eventually function as the basal disc sorts to the rear of the slug [15,63] (Fig. 1). During culmination, new stalk cells form at the tip, organizing into a stalk that pushes through the cell mass ultimately lifting it off of the substratum [15]. This pattern of stalk cell formation and slug morphogenesis can be radically altered by treatments with colchicine, a drug known to alter pattern formation and reverse polarity in a number of developing organisms [54]. In spite of its well established function as a microtubule depolymerizing agent, colchicine instead disrupts morphogenesis and induces stalk cell formation by altering calcium signal transduction leading to changes in gene expression and cell motility [66]. In keeping with colchicine's effect at increasing the production of stalk cells and inhibiting spore cell differentiation, the expression of prestalk specific genes such as ecmB are increased, and the pattern of cells

expressing them are significantly altered [66,67]. In the related species Polysphondylium pallidum, morphogenesis can also be altered by culturing developing cells in roller tube cultures [68]. Interestingly, in this experimental setup stalk cell formation can occur in the absence of an organized tip making the role of the ECM and tip epithelium in culmination less clear [68]. While no morphological tip is produced in spherical aggregates, a cAMP-synthesizing biochemical tip is present at the site of stalk cell formation, as well as the stalk cell enzyme alkaline phosphatase [68]. Identification of the ECM and cell adhesion components that regulate tip formation is needed to clarify this aspect of cell differentiation and morphogenesis during the culmination of Dictyostelium and related species. Interestingly, proteins required for tip formation in Dictyostelium are present in the sheath ECM (e.g., autophagy protein 16, TipD and defective in tip formation protein A, DtfA) [22]. TipD contains seven WD domains in its C-term (Pfam accession number: PF00400) (Fig. 2). The 40 amino acid WD domain is found in a number of eukaryotic proteins and is linked to a diversity of cellular processes [69,70]. The underlying function of WD domain-containing proteins is to coordinate the assembly of multi-protein complexes, by having the repeating units serve as a scaffold for protein interactions [71]. Thus in Dictyostelium, TipD may coordinate the assembly of protein complexes required for tip formation. Some WD domains also serve as ligandbinding sites [71]. Since TipD contains putative transmembrane domains (TMpred, ExPASy), it is also possible that TipD may function

R.J. Huber, D.H. O'Day / Biochimica et Biophysica Acta 1861 (2017) 2971–2980 Table 2 Domains identified in proteins detected in the Dictyostelium sheath ECM. dictyBase BLASTp search results Human protein

dictyBase ID

Thrombospondin 1 1170 aa Accession number: AAI36471

DDB0220137 Extracellular matrix protein A (EcmA) DDB0231389 EGF-like domain-containing protein Contains two EGF-like repeats; expressed in pstAB cells DDB0235162 Probable polyketide synthase 6 (Dipks6) DDB0237513 Uncharacterized protein C2 calcium-dependent membrane targeting domain-containing protein DDB0238302 Transmembrane, IPT, IG, E-set, repeat protein (TgrM1) IPT/TIG domain-containing protein; immunoglobulin E-set domain-containing protein DDB0220137 Extracellular matrix protein A (EcmA) DDB0231134 Cellulose-binding domain-containing protein DDB0231409 Protein disulfide isomerase 2 (Pdi2) DDB0266802 Dipeptidyl peptidase 3 (Dpp3) DDB0238658 Uncharacterized protein WSC domain-containing protein; SCP-like extracellular domain-containing protein; contains an N-terminal SCP domain that occurs in prokaryotic and eukaryotic proteins proposed to be Ca++ chelating serine proteases; contains two C-terminal WSC domains which are putative carbohydrate binding domains DDB0220030 Glycoprotein glucosyltransferase A (GgtA) DDB0220137 Extracellular matrix protein A (EcmA) DDB0232389 Putative cell surface glycoprotein DDB0238658 Uncharacterized protein WSC domain-containing protein; SCP-like extracellular domain-containing protein; contains an N-terminal SCP domain that occurs in prokaryotic and eukaryotic proteins proposed to be Ca++ chelating serine proteases; contains two C-terminal WSC domains which are putative carbohydrate binding domains DDB0231139 Extracellular matrix protein D (EcmD) DDB0238332 EGF-like domain-containing protein; C-type lectin domain-containing protein DDB0266344 Prespore-inducing factor E (PsiE)

von Willebrand factor 2715 aa Accession number: CCQ25771

Pro-epidermal growth factor isoform 1 preproprotein 1207 aa Accession number: NP_001954

Fibronectin isoform 1 preproprotein 2477 aa Accession number: NP_997647 Laminin 1193 aa Accession number: CAA78728

Protein

DDB0185040 Protein disulfide isomerase 1 (Pdi1) DDB0220137 Extracellular matrix protein A (EcmA) DDB0231389 EGF-like domain-containing protein Contains two EGF-like repeats; expressed in pstAB cells. DDB0232404 Prespore-inducing factor K (PsiK)

Alignments of human thrombospondin 1, human von Willebrand factor, human pro-epidermal growth factor isoform 1 preproprotein, human fibronectin isoform 1 preproprotein, and human laminin with the Dictyostelium proteome (BLASTp search on dictyBase, E-value set at 1000). Hits that localize to the sheath ECM are shown. Protein information was obtained from dictyBase (www.dictybase.org).

as a receptor. DtfA shares no significant homology with previously identified domains or proteins, but has been shown to be required for aggregation and tip formation during Dictyostelium development [72]. Together, these findings suggest that TipD and DtfA localize to the sheath ECM to regulate tip formation during Dictyostelium development. 6. Modulation of cell movement A number of ECM glycoproteins modulate cell migration in mammals. Some of the most well studied examples include tenascin C and laminin-5, whose EGFL repeats bind to the EGF receptor (EGFR) to

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increase the rate of cell movement [33,73–75]. In Dictyostelium, cells within the slug move in a chemotactic fashion towards cAMP, which is released by cells at the tip of the slug. However, how this movement of cells results in the movement of the multicellular slug is still not clear. There are several competing theories describing the way the slug moves [62]. One theory proposes that the forward migration of slugs is due to a ring of cells in the outer layer that attach to the surrounding ECM and the substratum [76]. In this model, the cells in the middle of the slug do not participate in slug migration since they are not able to obtain traction. Another theory is based on a ‘squeeze and pull’ mechanism, where cells in the anterior part of the slug gain traction by adhering firmly to the substratum [77]. Longitudinal contractions in the posterior region of the slug, and radial contractions of the outer cell layer, propel the slug forward. Finally, a third theory proposes that prestalk cells in the tip rotate perpendicular to the direction of slug migration in response to a rotating wave of cAMP [78,79]. These waves are then propagated to the rear of the slug driving the forward migration of prespore cells and ultimately the slug itself [79]. While the mechanistic role of the ECM in total slug movement remains to be clarified, its specific function in regulating the motility of individual cells within the slug is being detailed. In Dictyostelium, CyrA is secreted during development and localizes to the ECM [40–41] (Fig. 1). Extracellular processing of CyrA releases EGFL repeat-containing cleavage products that bind to the cell surface to modulate cell motility [40–45] (Fig. 1). Interestingly, EGFL repeatcontaining proteins are present in the sheath ECM, as are other proteins involved in regulating cell motility [22] (Table 1). While it is clear that EGFL repeats increase the motility of Dictyostelium cells, how this functions during development in general, and morphogenesis in particular, remains unclear. One interesting question is whether prestalk cells respond to and move quicker in response to EGFL repeats, thus contributing to the anterior sorting of this cell type. Early work in mammalian systems established the role of the ECM protein fibronectin in providing a migration pathway for neural crest cells by binding to integrins on the cell surface [80]. While there is no evidence to suggest that cell migration in Dictyostelium slugs involves such a mechanism, alignments of human fibronectin isoform 1 preproprotein and human laminin with the Dictyostelium proteome revealed several sheath ECM proteins with fibronectin- and laminin-like repeats (Table 2). Moreover, the adhesion proteins discoidin I and II share some sequence similarity to fibronectin [26,27]. Importantly, discoidin I and II are present in the sheath ECM [22]. Discoidin domain-containing proteins have been identified in a number of systems and function in a diversity of cellular processes including cell adhesion, chemotaxis, proliferation, and ECM remodelling [81–83]. Not surprisingly, some of these proteins are linked to human disease [82,83]. Dictyostelium also contains proteins similar to the integrin beta family (SibA, SibB, SibC, SibD, SibE) that bind to talin via their cytosolic domain, and are involved in phagocytosis and substrate adhesion during development [84,85]. However, whether the Sib proteins and integrins share a common ancestor or whether they evolved independently is not currently known [38]. Nonetheless, future research on the potential interaction between discoidins and the Sib proteins in Dictyostelium may be able to shed light on the mechanism regulating the movement of cells within the slug, and ultimately the slug itself. 7. Regulation of developmental events In mammals, the ECM plays an important role in regulating cell differentiation and branching morphogenesis [1]. For example, laminins regulate cell-ECM interactions during intestinal morphogenesis and differentiation, and tenascin C promotes glial cell differentiation by activating Wnt signal transduction [86,87]. During Dictyostelium development, several diffusible morphogens regulate differentiation including various differentiation-inducing factors (DIFs), cAMP, ammonia, and other secreted factors [88]. Prestalk cell differentiation is stimulated

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by DIF-1, with adenosine playing a synergistic role in repressing prespore cell differentiation, while prespore cell differentiation is stimulated by cAMP and ammonia [88]. While the role of the ECM in maintaining, storing, or concentrating levels of these factors has not been studied, other developmental factors have been shown to localize and/or be generated within the ECM. Spore differentiation factors 1 and 2 (SDF-1 and SDF-2) are two such secreted peptides that induce spore cell differentiation [89] (Fig. 1). The acyl-CoA binding protein (AcbA), which is cleaved by the membrane-bound serine protease TagC to generate SDF-2, is present in the sheath ECM [22,90]. In prespore cells, glutamate decarboxylase (GadA) generates GABA from glutamate [91]. GABA then binds to a seven transmembrane G-protein-coupled GABA(B)-like receptor (GrlE) causing the release of AcbA from prespore cells [91]. GABA also stimulates TagC on the surface of prestalk cells, which in turn generates SDF-2 from AcbA [91] (Fig. 1). Since GABA is a well-established neurotransmitter in the mammalian nervous system, Dictyostelium presents an excellent model for studying the function of GABA as an intercellular signalling molecule. As yet the interplay between SDF-2 and the other factors has not been revealed. Proteomic profiling of the sheath ECM revealed a number of proteins linked to cell differentiation and morphogenesis [22] (Table 1). In addition, Loomis [92] recently reviewed the known proteins that regulate morphogenesis in Dictyostelium. Several of these proteins localize to the sheath ECM including cellulose synthetase (DcsA), EcmA, and EcmD [22]. Of the 16 proteins linked to culmination, only AcbA localizes to the sheath ECM [22]. The prespore-inducing factors (Psi) comprise a family of 19 PA14 domain-containing proteins in Dictyostelium (PsiA-S, www.dictybase. org). The PA14 domain (Pfam accession number: PF07691), which has a β-barrel structure, is proposed to function as a carbohydrate-binding module [93]. Interestingly, like EcmA, 14 of the 19 Psi proteins also contain CTDC domains. Of the 19 Psi proteins in Dictyostelium, five have been verified as secreted factors (PsiC, PsiE, PsiI, PsiK, PsiM) [20]. Of those five proteins, PsiE, PsiK, and PsiM specifically localize to the sheath ECM [22]. PsiE, PsiK, and PsiM each contain a signal sequence, a PA14 domain, and a C-terminal cysteine-rich region (Fig. 2). Research on CyrA, which contains three CTDC domains, suggests that a main function for this domain may be to modulate cell motility [40–45]. The presence of PsiE, PsiK, and PsiM in the ECM, coupled with recent research on CyrA, suggests that these proteins may modulate the movement of prespore cells prior to terminal differentiation. Together these findings indicate that much still remains to be discovered about the Dictyostelium ECM and how the proteins contained within regulate cell differentiation and morphogenesis. 8. Proteolytic processing within the extracellular matrix Proteolytic cleavage of ECM components to generate bioactive fragments is a normal process that regulates a number of cellular processes in mammals [94]. For example, bioactive peptides released from collagen I attract neutrophils to sites of inflammation [95]. However, aberrant processing of ECM components can result in pathogenesis. For example, altered processing of tenascin C, TSP-1, and laminin-5 is linked to the metastasis of cancer cells in humans [74,96,97]. Proteolytic processing of these proteins releases EGFL repeating-containing fragments that bind to the cell surface and increase the rate of cell motility [33,34,75,98]. For tenascin C, the 14th EGFL repeat from the N-terminal end (Ten14) increases cell motility by binding to the EGFR [33,73]. Moreover, processing of tenascin C by the metalloprotease meprinβ releases cleavage products that suppress the oligomerization and anti-adhesive activity of the protein resulting in increased cell spreading [99]. Early work in Dictyostelium revealed the presence of low molecular weight peptides in the sheath ECM suggesting that peptide signalling may play an important role in regulating cellular processes within the slug [5]. Interestingly, research on CyrA and AcbA suggests that

proteolytic processes occur in the Dictyostelium ECM during development, but that proteolytic events in general likely occur after proteins have been incorporated into the ECM [8]. While the protease responsible for AcbA cleavage has been identified (i.e., TagC), it is still not known how CyrA is processed to release EGFL repeat-containing products that bind to the cell surface to modulate cell motility. Importantly, previous studies have shown that a number of proteases are secreted and localize to the sheath ECM during development, including puromycin-sensitive aminopeptidases (PsaA and PsaB), which could be involved in CyrA processing [20,22,100,101] (Fig. 1; Table 1). Future research in this area may be able to reveal how proteolytic processing of ECM components regulates Dictyostelium development. 9. Calcium and calmodulin signalling within the extracellular matrix Several calcium-binding proteins (CaBPs) and CaMBPs are present extracellularly during growth and multicellular development in Dictyostelium [20,22,40,41]. Interestingly, CaM has also been detected extracellularly where it is thought to function as a modulator of growth, cAMP chemotaxis, and proteolysis through its interaction with specific CaMBPs [20,22,40,102]. While there is evidence to suggest that CaM itself localizes to the ECM [41], it was not detected in a proteomic analysis of the sheath ECM possibly because it is too small a protein to be contained at detectable levels [22]. Research on extracellular CaM and CaMBPs in other systems is limited. In plants, extracellular CaM regulates pollen germination and tube formation [103]. Research on frog nerve cells suggests that extracellular CaM inhibits the outgrowth of sensory axons and the injury-induced proliferation of non-neuronal cells [104]. Finally in mammals, extracellular CaM enhances phospholipid-associated vasoactive intestinal peptidemediated vasodilation [105]. Protein secretion in Dictyostelium can proceed via two pathways. Proteins that contain a signal sequence for secretion follow the conventional mechanism involving the endoplasmic reticulum (ER), transport through the Golgi, and secretion via vesicle release. The alternative pathway is an unconventional mechanism involving the Golgi reassembly stacking protein (GRASP) and the contractile vacuole (CV) system [106,107]. This mode of secretion has been well-studied for AcbA and Cad1, which both lack a signal sequence for secretion, but localize to the sheath ECM [22,106,108,109]. While some CaMBPs such as CyrA contain a signal sequence for secretion, some, including CaM itself, do not [40,110]. Intriguingly, CaM localizes predominantly on the membranes of the CV system and mediates the secretion of Cad1 [109,111]. These results suggest that the CV system regulates the unconventional secretion of CaM, and CaMBPs lacking signal sequences for secretion, during Dictyostelium growth and development. Proteomic profiling also revealed the presence of a number of CaBPs in the sheath ECM. Some examples include alpha-1,2-mannosidase, Cad1, Cad3, calcium-binding protein 4b (Cbp4b), calcium-binding protein A (CbpA), calcium-binding protein G (CbpG), calfumirin-1, and calreticulin [22]. The same analysis also revealed a number of CaMBPs including Cad1 and Ras GTPase-activating-like protein (RgaA) [22]. Together, these observations suggest that calcium and/or CaM signalling within the sheath ECM may be important for processes that occur during Dictyostelium development. Moreover, these results indicate that research in Dictyostelium could provide valuable insight into the function of extracellular CaM and CaMBPs in other systems. 10. Nuclear, ribosomal, and metabolic proteins within the extracellular matrix A large number of ribosomal and nuclear proteins were detected in conditioned media from developing Dictyostelium cells and the sheath ECM [20,22]. Previous work has shown that the sheath ECM does not contain significant amounts of the cytoskeletal proteins β-actin and

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α-tubulin or the nuclear/cytoplasmic protein Cdk5 [6,22,40,41]. Therefore, the presence of cytoplasmic and nuclear proteins in the sheath ECM is likely not due to cell lysis or death. The extracellular release of certain intracellular proteins could be an evolutionarily primitive way of turning over large amounts of proteins that are no longer needed. For example, ribosomal proteins that are essential for growth are not necessarily needed during differentiation. With a short developmental time period, and the need to only ensure the survival of a sub-population of presumptive spore cells, simply dumping excess cellular components rather than turning them over might be a valid response. Like Dictyostelium, histones have been detected extracellularly in mammals where they function to induce chemokine production and recruit leukocytes during inflammatory and/or necrotic conditions [112]. Kriebel et al. [113] showed that the presence of extracellular ribosomal proteins in Dictyostelium could be due to multivesicular body secretion during development, which would be an efficient mechanism for getting rid of this major cellular component as well as others. Proteomic profiling also revealed that a large number of secreted proteins and ~50% of sheath ECM proteins are linked to metabolic processes (Table 1) [20,22]. While the biological explanation for the presence of such a large number of metabolic proteins within the sheath ECM is unclear, in mammals, aberrant modulation of cellular metabolism by the ECM is linked to tumorigenesis [114]. Finally, the large number of proteins of unknown function secreted during development and detected in the ECM indicates that future research on the Dictyostelium ECM may be able to shed light on the functions of these proteins [20,22] (Table 1). 11. Extracellular matrix proteins of Dictyostelium and human disease In mammalian cells, binding of EGF to the EGFR activates signalling pathways that modulate a diversity of cellular processes, and alterations in EGF/EGFR signalling are linked to many human cancers [115–117]. As detailed above, EGFL repeat-containing polypeptides generated in the Dictyostelium ECM through proteolytic cleavage of ECM proteins, regulate cell motility via signalling mechanisms that involve components known to regulate EGF-enhanced cell movement in mammals (e.g., Ras proteins, protein kinase A, PI3K, CaM, Ca2 +) [117–122]. While many of the components of the intracellular signalling cascade in Dictyostelium have been revealed [123], there are still aspects that

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remain unclear. For example, in mammalian systems, some EGFL repeats increase the rate of cell motility by binding to the EGFR and activating intracellular signal transduction [33,34]. While there is no evidence to suggest that the Dictyostelium genome encodes an EGFRlike protein, a specific EGFL repeat from CyrA has been shown to bind to the cell surface [41]. Moreover, the Dictyostelium genome contains a higher percentage of proteins with EGFL repeats than any other sequenced eukaryote [39]. The identification of the EGFL repeat receptor in Dictyostelium could provide new insight into how EGFL repeats modulate cellular processes during Dictyostelium development. Dictyostelium has recently gained interest as a system for the study of amyloid neurodegenerative diseases including Alzheimer's (AD), Huntington's (HD) and Parkinson's (PD) [124–126]. Proteins containing certain repeated sequences—especially glutamine (Q) and asparagine (N)—increase the susceptibility for amyloid production. Interestingly, Dictyostelium has an enriched Q/N proteome [124,125]. In spite of this, amyloid accumulation does not occur in this eukaryotic microbe. More to the point, expression of an expanded version of human huntingtin exon 1 (Q103) or yeast prion protein Sup35 (NM) fail to generate insoluble deposits in Dictyostelium [124]. However, if molecular chaperones are compromised, these proteins will aggregate and become cytotoxic [124]. In keeping with this, research by a diversity of groups has shown that a critical protein in the breakdown of toxic elements linked to AD, HD and PD is PSA. PSA is the only mammalian enzyme capable of digesting the PolyQ sequences underlying HD [127]. Overexpression of PSA in human neuroblastoma SH-SY5Y (nPSA/TauP301L) cells reduced toxic tau neurofibrillary tangles and delayed the onset of behavioural effects, while underexpression resulted in enhanced protein accumulation [128]. PSA also appears to play a critical role in the toxicity of Aβ, the central component of amyloid plaques. Using a genetic screen in Drosophila, Kruppa et al. [129] showed that PSA functions as a potent suppressor of Aβ toxicity. The Dictyostelium genome encodes two PSAs (PsaA and PsaB) of which only PsaA has been studied in any detail. PsaA localizes to the nucleus, cytoplasm, and the ECM [22,130–133] (Fig. 1). While the nuclear and cytoplasmic localization of PsaB has not yet been verified, like PsaA, it is also secreted and present in the sheath ECM [20,22]. The identification of PsaA as a nuclear, cytoplasmic and extracellular constituent, along with attributes listed above, adds to the potential value of using Dictyostelium for the study of amyloid-based neurodegenerative diseases. A full understanding of

Fig. 3. Summary of the known components and events mediated by the sheath ECM of Dictyostelium. Like mammals, during multicellular development, Dictyostelium cells release precursor proteins that are proteolytically processed to release bioactive peptides that regulate cell motility and differentiation. Matricellular proteins have been identified that regulate cell motility. Structural and cell adhesion proteins maintain the multicellular status of the aggregate, while the functional roles of the many signalling proteins remain to be analyzed. Based on research in mammals, matricellular proteins could function to mediate these signalling events. Other known roles of mammalian ECM proteins (e.g., morphogenetic functions) have so far not been sufficiently analyzed in Dictyostelium.

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the pathways involved in preventing amyloid accumulation in Dictyostelium could provide novel routes to tackling these dreaded neurological disorders. 12. Conclusion Clearly the ECM is a complex and dynamic structure that is involved in regulating a number of cellular processes. It contains both structural and non-structural components and undergoes dramatic remodelling to facilitate these processes. The Dictyostelium ECM shares many of the features of mammalian and plant ECM, and thus presents an excellent system for studying the structure and function of the ECM. For the most part, our understanding of the functions of the ECM in Dictyostelium has been revealed through indirect studies. In spite of this, a great deal has been learned about the diverse roles the ECM plays in this social amoebozoan (Fig. 3). Recent research shows that matricellular proteins exist in Dictyostelium. Similarly, the formation of bioactive fragments from ECM proteins has been identified by various labs. Like mammals, several verified growth and differentiation factors are generated by proteolytic processing of protein precursors within the Dictyostelium ECM. Motilityenhancing EGFL repeat-containing polypeptides generated within the Dictyostelium ECM operate in essentially the same way as those in mammalian cells by binding to the cell surface and activating intracellular signal transduction. Future research on the Dictyostelium ECM may be able to reveal new matricellular proteins, proteases that mediate the processing of ECM components, and the functions of the many uncharacterized proteins detected in the ECM. Finally, the ECM of this genetically tractable organism also holds much promise for yielding basic biological insight into human diseases such as cancer and neurodegeneration. Transparency document The Transparency document associated with this article can be found, in the online version. Acknowledgments This review was supported by internal funds provided by Trent University (R.J.H.) and a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (A6807 to D.H.O'D). The funders had no role in study design, data collection and analysis, interpretation of data, decision to publish, or writing of the manuscript. References [1] C. Bonnans, J. Chou, Z. Werb, Remodelling the extracellular matrix in development and disease, Nat. Rev. Mol. Cell Biol. 15 (2014) 786–801. [2] R.O. Hynes, Stretching the boundaries of extracellular matrix research, Nat. Rev. Mol. Cell Biol. 15 (2014) 761–763. [3] C. Zeltz, D. Gullberg, Post-translational modifications of integrin ligands as pathogenic mechanisms in disease, Matrix Biol. 40 (2014) 5–9. [4] Q. Du, Y. Kawabe, C. Schilde, Z.H. Chen, P. Schaap, The evolution of aggregative multicellularity and cell-cell communication in the Dictyostelia, J. Mol. Biol. 427 (2015) 3722–3733. [5] H. Freeze, W.F. Loomis, Isolation and characterization of a component of the surface sheath of Dictyostelium discoideum, J. Biol. Chem. 252 (1977) 820–824. [6] E. Smith, K.L. Williams, Preparation of slime sheath from Dictyostelium discoideum, FEMS Microbiol. Lett. 6 (1979) 119–122. [7] W.N. Grant, K.L. Williams, Monoclonal antibody characterisation of slime sheath: the extracellular matrix of Dictyostelium discoideum, EMBO J. 2 (1983) 935–940. [8] C.M. West, G.W. Erdos, The expression of glycoproteins in the extracellular matrix of the cellular slime mold Dictyostelium discoideum, Cell Differ. 23 (1988) 1–16. [9] D.H. O'Day, Cell differentiation during fruiting body formation in Polysphondylium pallidum, J. Cell Sci. 35 (1979) 203–215. [10] M.R. Wilkins, K.L. Williams, The extracellular matrix of the Dictyostelium discoideum slug, Experientia 51 (1995) 1189–1196. [11] D.J. Dickinson, D.N. Robinson, W.J. Nelson, W.I. Weis, α-Catenin and IQGAP regulate myosin localization to control epithelial tube morphogenesis in Dictyostelium, Dev. Cell 23 (2012) 533–546. [12] B.M. Shaffer, Cell movement within aggregates of the slime mould Dictyostelium discoideum revealed by surface markers, J. Embryol. Exp. Morpholog. 13 (1965) 97–117.

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