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Novel roles for collagens in wiring the vertebrate nervous system
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Novel roles for collagens in wiring the vertebrate nervous system Michael A Fox Wiring the vertebrate nervous system is a multi-step process that relies heavily upon the role of transmembrane and extracellular adhesion molecules. Despite the extensive attention focused on such molecules, collagens, a large family of structural adhesion molecules expressed in the vertebrate nervous system, have been largely overlooked for roles in neural circuit formation. Recently, however, several studies have unexpectedly identified novel roles of collagens and collagen-like molecules in the developing vertebrate nervous system. Here, contributions of these collagens and collagenlike molecules in neural circuit formation are reviewed. Address Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, PO Box 98-0709, Richmond, VA 23298-0709, United States Corresponding author: Fox, Michael A ([email protected])
Current Opinion in Cell Biology 2008, 20:508–513 This review comes from a themed issue on Cell-to-cell contact and extracellular matrix Edited by Mark Ginsberg and Jean Schwarzbauer Available online 21st June 2008 0955-0674/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2008.05.003
Introduction Proper functioning of the vertebrate nervous system requires the formation of a highly complex and precise network of neural connections. The formation of these connections relies heavily upon the ability of a neuron to receive and process cues from surrounding neurons, glia, and/or extracellular matrix (ECM). Such cues, in the form of transmembrane adhesion molecules and extracellular factors (i.e. morphogens, growth factors, and extracellular adhesion molecules) direct the four main steps of neural circuit formation—axon outgrowth, target selection, synaptic differentiation, and synaptic maintenance and refinement (Figure 1) [1–4]. Despite the current attention transmembrane and extracellular adhesion molecules receive, collagens, a large family of structural adhesion molecules, have been largely overlooked for active roles in circuit formation and refinement. Collagens are triple helical, ECM molecules assembled from three separate polypeptide (a) chains. Each a chain contains repeating Gly-X-Y peptide sequences—the Current Opinion in Cell Biology 2008, 20:508–513
defining feature of the collagen family of proteins [5,6]. In vertebrates, 47 mammalian genes encode collagen a chains and >30 genes encode collagen-like molecules— molecules containing collagenous domains (i.e. Gly-X-Y repeats) but named for other domains or functions (Table 1). Outside of the nervous system, collagens have been extensively studied for their roles as structural molecules and are best known for their ability to assemble into elongated fibers and add tensile strength to tissue. Over the past two decades, however, interest in non-structural activities of collagens has arisen for at least two reasons. Firstly, many recently discovered collagens and collagenlike molecules are not assembled into structural fibers [5,6]. Genes coding for both non-fibril-forming collagens and collagen-like molecules outnumber the 13 fibrilforming collagen genes (Table 1). Secondly, non-collagenous (NC) domains can be proteolytically shed from collagen a chains and can exhibit unconventional bioactivities, unrelated to the structural roles of the collagen from which they were released [7,8]. Thus, collagens are not merely structural molecules but are bio-active adhesion molecules. Non-fibril-forming collagens and collagen-like proteins are widely expressed in both the peripheral and central nervous systems, and are even expressed by neurons (e.g. [9,10–14,15,16–18]). However, their functions in neural development, and specifically in neural circuit formation, have remained relatively unclear. In vitro assays have implicated collagens and collagen-like molecules in contributing to neural cell migration, differentiation, and neurite outgrowth [19,20]. In addition to in vitro assays, invertebrate studies support roles for collagens in neural development: genetic disruption of the NC1/endostatin domain of the C. elegan collagen XVIII homolog, cle-1, causes defects in motor axon guidance and organization of neuromuscular junctions (NMJs)— synapses between motoneurons and muscle fibers [21,22]. Only recently, however, have in vivo roles for collagens and collagen-like molecules been identified in each of the four steps required for vertebrate neural circuit formation.
Axon outgrowth: collagen XVIII and diwanka (lh3) regulate motor axon outgrowth A first step in neural circuit formation is for a neuron to extend an axon in search of a potential synaptic partner. On the basis of its role in C. elegans axon guidance [21] and its expression during periods of motor axon outgrowth [23], collagen XVIII was a promising candidate to regulate www.sciencedirect.com
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Figure 1
zebrafish motor axon outgrowth. Collagen XVIII, encoded by the col18a1 gene in vertebrates, is a heparan sulfate proteoglycan. Proteolytic processing of collagen XVIII releases a non-collagenous bio-active fragment, termed endostatin [6–8]. By blocking col18a1 translation with anti-sense morpholino oligonucleotides, Schneider and Granato recently showed that pioneering motor axons (termed primary motor axons) exit the spinal cord but fail to extend along their normal stereotyped pathways in the absence of collagen XVIII (Figure 2a–c) [24]. Similar to findings seen with col18a1 suppression, axons either fail to exit the spinal cord or stop extending within the common path in another zebrafish mutant, diwanka (Figure 2a, b, and d) [25,26]. Diwanka mutations were recently mapped to the lysyl hydroxylase 3 gene (lh3), which encodes a multifunctional enzyme necessary for post-translationally modifying collagen molecules [5,24,27]. Although other lh genes are highly expressed in embryonic zebrafish muscle, lh3 expression temporally corresponds with motor axon outgrowth and is restricted to col18a1-expressing cells adjacent to the common path [23,24]. On the basis of similar expression patterns and phenotypes, it is tempting to speculate that specific modifications of collagen XVIII by lysyl hydroxylase 3 may influence vertebrate motor axon outgrowth.
Target selection: dragnet (col4a5) is required for layer-specific targeting
Four steps of neural circuit formation.
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As growing axons approach their destination, they must choose an appropriate target. Target selection includes both choosing a specific region to arborize in and a cell to connect with. Synapses between the retina and brain (i.e. either retino-tectal and retino-geniculate synapses) have proved useful for studying target specificity since retinal axons arborize in specific and discrete regions of the tectum or lateral geniculate nucleus (LGN; Figure 2e, f, and k). In zebrafish embryos, growing retinal axons terminate in one of four main retinorecipient tectal layers (Figure 2e and f). Forward genetic screens have identified several putative genes that regulate retino-tectal architecture [28–30]. In one case, Baier and colleagues mutagenized a line of brn3c-GFP transgenic zebrafish, which express GFP in a subset of retinal axons, and identified dragnet, a mutant with mistargeted retinal arbors within the tectal (Figure 2e–h) [30]. Genetic mapping identified the dragnet gene as col4a5—which encodes the a5 chain of collagen IV, a network-forming non-fibrillar collagen [31,32]. Several lines of evidence suggest that dragnet (col4a5) gene activity is required for axon targeting and not outgrowth: Firstly, dragnet axons reach appropriate retinorecipient tectal layers, but sprout promiscuously into inappropriate layers [31]; secondly, injection of collagenase into wild-type tectum after retinal axons arborize within the tectum, phenocopies defects observed in dragnet mutants [31]; thirdly collagen IV does not support retinal axon outgrowth in vitro Current Opinion in Cell Biology 2008, 20:508–513
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Table 1 Collagens and collagen-like molecules Collagen superfamily Fibril-forming collagens Collagen I (col1a1 and col1a2) Collagen II (col2a1) Collagen III (col3a1) Collagen V (col5a1, col5a2, col5a3 and col5a4) Collagen XI (col11a1 and col11a2) Collagen XXIV (col24a1) Collagen XXVII (col27a1)
FACIT and related collagens Collagen IX (col9a1, col9a2 and col9a3) Collagen XII (col12a1) Collagen XIV (col14a1) Collagen XVI (col16a1) Collagen XIX (col19a1) Collagen XX (col20a1) Collagen XXI (col21a1) Collagen XXII (col22a1)
Beaded filament-forming collagens Collagen VI (col6a1, col6a2, col6a3, col6a4, col6a5 and col6a6) Collagen XXVI (col26a1) Emu2 Collagen XXVIII (col28a1) Collagen XXIX (col29a1)
Transmembrane collagens Collagen XIII (col13a1) Collagen XVII (col17a1) Collagen XXIII (col23a1) Collagen XXV (col25a1)
Network-forming collagens Collagen IV (col4a1, col4a2, col4a3, col4a4, col4a5 and col4a6) Collagen VIII (col8a1 and col8a2) C1q Collagen X (col10a1) C1q
Multiplexin collagens Collagen XV (col15a1) Collagen XVIII (col18a1) Anchoring fibril-forming collagen Collagen VII (col7a1)
Collagen-like proteins C1q/TNF superfamily proteins Complement C1q Hibernation proteins (HP20, HP25 and HP27) Emilin 1 Emilin 2 Adiponectin (Acrp30) CORS26 (CTRP3) C1q/TNFa-Related Proteins (CTRP1, CTRP2, CTRP4, CTRP5, CTRP6 and CTRP7) Ectodysplasin A Saccular collagen
Collectins and Ficolins Mannan-binding lectin Surfactant protein-A Surfactant protein-D Collectin-L1 Collectin-P1 Collectin-43 kDa Collectin-46 kDa Conglutinin L-ficolin M-ficolin H-ficolin
Emilin and multimerin 1 (Emu1)
Src-homologous and collagen protein (Shc)
Macrophage receptors Class A scavenger receptors (Types I, II, III) MARCO
Cementum-derived attachment protein Collagenous subunit of acetyl-cholinesterase (colQ) *
Gliomedin Vertebrate collagen molecules are classified by type, designated by roman numerals. Genes coding for a chains contributing to collagen types are italicized in parentheses. Types of collagens are subdivided on the basis of their supramolecular assembly (i.e fibril-forming, beaded filamentforming, network-forming, or anchoring fibril-forming collagens) or their structure and function (i.e. transmembrane collagens, fibril associated collagen with interrupted triple helices [FACIT], or multiplexins) [5,6,42]. In addition to the 47 vertebrate genes that code for collagens, over 30 vertebrate genes code for collagen-like proteins [5,6,43–47]. Several collagens can also be classified with collagen-like proteins: collagen XXVI is also called Emu2 (emilin and multimerin 2) [47,48]; collagen VIII and X contain C1q globular domains (gC1q) and are members of the C1q/TNF superfamily (Kishore et al. 2004). * Unlike other collagen-like molecules, acetylcholinesterase has separate genes that code for either the enzymatic or collagenous subunits [49].
[33]. Thus, dragnet (col4a5) is necessary for targeting and confining retinal axons into appropriate tectal layers. Interestingly col4a5 mRNA is absent from zebrafish tectum, but is expressed in the epidermis covering the tectum [31]. This suggests that non-neural cells assemble a collagen a5(IV)-containing ECM that contributes to the targeting and active confinement of retinal arbors to correct tectal layers. This collagen a5(IV)-rich ECM must therefore be repulsive to some brn3c-positive Current Opinion in Cell Biology 2008, 20:508–513
retinal axons (Figure 2e and g) but attractive to others (Figure 2f and h).
Synaptic differentiation: NC1 domains of collagen IV direct nerve terminal formation and maintenance After contacting appropriate targets, axons and targets must differentiate together into functioning synapses—a process termed synaptic differentiation [1]. Precise www.sciencedirect.com
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Figure 2
coordination of pre- and postsynaptic differentiation suggests that trans-synaptic organizing signals are passed between axon and target. At the NMJ, these trans-synaptic cues are embedded in a specialized basal lamina (BL) lying within the synaptic cleft [34]. Two such extracellular cues, laminin b2 and agrin, are required for pre- and postsynaptic differentiation, respectively [1]. NMJs in mice lacking laminin b2 appear normal at birth but nerve terminals fail to mature perinatally, suggesting other factors contribute to presynaptic differentiation [9,35]. To identify such factors, Sanes and colleagues biochemically fractionated synaptic BL extracts and sought fractions capable of inducing presynaptic differentiation in cultured MNs [9]. One active fraction was identified as the NC1 domain of a collagen IV [9]. Mammalian genomes contain six genes encoding collagen a(IV) chains [32], however, only a2, a3, and a6(IV) NC1 domains exhibit synaptogenic activity in vitro [9]. Of these active a chains, only collagen a2(IV) is present as NMJs form. Motor nerve terminals in mice with reduced levels of a2(IV) have improperly clustered synaptic vesicles and excess nerve terminal sprouts, suggesting a role for a2(IV) in nerve terminal formation in vivo (Figure 2j) [9]. In mice lacking the a3 and a6(IV) chains, which normally appear at synapses postnatally, nerve terminals are improperly maintained [9]. Thus, although all 3 NC1 domains share similar bio-activities in vitro, a2 (IV) chains are necessary for nerve terminal formation and a3 and a6(IV) chains are necessary for actively maintaining nerve terminals in vivo.
Synaptic refinement: C1q refines synaptic connections in the CNS Since an excess of immature synapses initially form in the vertebrate nervous system, appropriate synaptic connections must be maintained while inappropriate connections must be pruned. While the process of synaptic refinement is regulated by neuronal activity [36], the molecular elements regulating this process are not well characterized. Recently, however, Barres and colleagues
Neural phenotypes associated with the loss of vertebrate collagens or collagen-like proteins. (a–d) Collagen XVIII and diwanka are required for motor axon outgrowth. (a) A cross section through a zebrafish embryo demonstrates that three primary motor axons (black, red, and purple) exit the spinal cord (gray) and initially following a similar path, called the common path. Ultimately each axon projects along a unique, stereotyped path within muscle (blue) [50]. (b) Viewed laterally, projections of two primary motor axons are easily observed. (c and d) In embryos with reduced col18a1 (col18a1MO) or mutated lh3 (diwanka), primary motor axons fail to extend beyond the common path. (e–h) Dragnet (col4a5) is required for layer-specific targeting of retino-tectal www.sciencedirect.com
projections. Zebrafish retinal ganglion cell (RGC) axons (black) project from the eye (gray) to one of four layers in the tectum. (e and f) Classes of RGCs expressing Brn3c extend their axons specifically into one of the two tectal layers. (g and h) In the absence of dragnet, Brn3c-positive axons trespass into inappropriate tectal layers. (i and j) Collagen IV is required for mammalian nerve terminal formation. (i) After motor axons (blue) find appropriate target muscle fibers (gray), pre- and postsynaptic differentiation ensues: synaptic vesicles (purple) aggregate in nerve terminals and neurotransmitter receptors (red) cluster in postsynaptic membranes. (j) In mice with reduced levels of collagen IV (col4a1Dex40; see reference [9]), synaptic vesicles fail to properly cluster and sprouts extend beyond the synapse. (k–m) Mammalian retino-geniculate synapse elimination requires C1q. (k) Retinal axons from both eyes (gray) innervate eye-specific domains of each LGN. Blue and lavender indicate regions of each LGN innervated by a given eye. (l) In neonate LGN, retinal inputs from each eye have overlapping arbors (striped region), however, inputs are pruned so that non-overlapping, eye-specific domains are present in the mature LGN. (m) In the absence of C1q, eyespecific segregation is impaired. Current Opinion in Cell Biology 2008, 20:508–513
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revealed a novel role for the collagen-like protein C1q in eliminating inappropriate synapses in the mammalian visual system [15]. Unexpectedly, immature astrocytes induce the expression of C1q, classically an immune molecule, in retinal ganglion cells during normal periods of synaptic refinement [15]. At early postnatal ages in mice, retinal projections from the two eyes are diffusely organized and share terminal space in their target structure, the LGN (Figure 2l) [37]. However, during the first two weeks of life these retinal inputs prune and segregate so the mature LGN has non-overlapping eye-specific domains (Figure 2k and l) [37,38]. In the absence of C1q, this eye-specific segregation is impaired, so that projections remain diffuse and a single LGN cell continues to receive multiple inputs (Figure 2m) [15]. How C1q mediates synaptic refinement in the LGN remains unclear. On the basis of its immunological role in the classical complement cascade [39], C1q might label synapses to be phagocytosed (and thus eliminated) by microglial cells. Whether the collagenous domain of C1q directly contributes to this activity remains unclear, however, it is noteworthy that microglial cells express C1qRp—a receptor that binds the collagenous domain of C1q to enhance phagocytosis [40,41].
Conclusions
4.
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9.
Fox MA, Sanes JR, Borza DB, Eswarakumar VP, Fassler R, Hudson BG, John SW, Ninomiya Y, Pedchenko V, Pfaff SL et al.: Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell 2007, 129:179-193. The authors were the first to demonstrate that NC1 domains of collagen IV influence nerve terminal assembly and maintenance. Moreover, the authors demonstrate that laminin b2 and the FGF7 subfamily also contribute to presynaptic differentiation, and that all three sets of presynaptic organizers act sequentially to form and maintain nerve terminals at the NMJ.
10. Eshed Y, Feinberg K, Poliak S, Sabanay H, Sarig-Nadir O, Spiegel I, Bermingham JR Jr, Peles E: Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron 2005, 47:215-229. The authors identify gliomedin, a Schwann cell-derived collagen-like ligand for neurofascin and NrCAM at peripheral nodes of Ranvier. In vitro experiments demonstrate gliomedin is necessary and sufficient for node formation.
Here, novel roles for collagens and collagen-like molecules in the formation of vertebrate neural circuits have been reviewed [9,15,24,31] The most surprising aspect of the studies reviewed here is the role of collagens in the vertebrate CNS [15,31]. Collagens have long been overlooked for roles in the mammalian brain since neither collagen fibers nor collagen-rich BLs are present in the CNS. However, it is now clear that non-fibril-forming collagens and collagen-like molecules are expressed in the vertebrate CNS, and in some cases are even expressed by neurons. Although the studies highlighted here begin to shed light on potential roles for collagens in the CNS, future studies are needed to identify functions for the many other neural collagens expressed in the vertebrate brain.
11. Claudepierre T, Manglapus MK, Marengi N, Radner S, Champliaud MF, Tasanen K, Bruckner-Tuderman L, Hunter DD, Brunken WJ: Collagen XVII and BPAG1 expression in the retina: evidence for an anchoring complex in the central nervous system. J Comp Neurol 2005, 487:190-203.
Acknowledgements
15. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B et al.: The classical complement cascade mediates CNS synapse elimination. Cell 2007, 131:1164-1178. This study reveals a novel role for complement C1q in synapse elimination in the mammalian CNS. Although neuronal C1q is normally downregulated after periods of synaptic refinement, this study reveals C1q expression is upregulated in early stages of glaucoma. Re-expression of C1q in the adult nervous system may therefore contribute to synaptic (and perhaps neuronal) loss associated with glaucoma.
I am extremely thankful to JW Bigbee, J Dennis, W Guido, and H Umemori for their constructive comments on this manuscript.
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Current Opinion in Cell Biology 2008, 20:508–513
Novel roles for collagens in wiring the vertebrate nervous system Michael A Fox Wiring the vertebrate nervous system is a multi-step process that relies heavily upon the role of transmembrane and extracellular adhesion molecules. Despite the extensive attention focused on such molecules, collagens, a large family of structural adhesion molecules expressed in the vertebrate nervous system, have been largely overlooked for roles in neural circuit formation. Recently, however, several studies have unexpectedly identified novel roles of collagens and collagen-like molecules in the developing vertebrate nervous system. Here, contributions of these collagens and collagenlike molecules in neural circuit formation are reviewed. Address Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, PO Box 98-0709, Richmond, VA 23298-0709, United States Corresponding author: Fox, Michael A ([email protected])
Current Opinion in Cell Biology 2008, 20:508–513 This review comes from a themed issue on Cell-to-cell contact and extracellular matrix Edited by Mark Ginsberg and Jean Schwarzbauer Available online 21st June 2008 0955-0674/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2008.05.003
Introduction Proper functioning of the vertebrate nervous system requires the formation of a highly complex and precise network of neural connections. The formation of these connections relies heavily upon the ability of a neuron to receive and process cues from surrounding neurons, glia, and/or extracellular matrix (ECM). Such cues, in the form of transmembrane adhesion molecules and extracellular factors (i.e. morphogens, growth factors, and extracellular adhesion molecules) direct the four main steps of neural circuit formation—axon outgrowth, target selection, synaptic differentiation, and synaptic maintenance and refinement (Figure 1) [1–4]. Despite the current attention transmembrane and extracellular adhesion molecules receive, collagens, a large family of structural adhesion molecules, have been largely overlooked for active roles in circuit formation and refinement. Collagens are triple helical, ECM molecules assembled from three separate polypeptide (a) chains. Each a chain contains repeating Gly-X-Y peptide sequences—the Current Opinion in Cell Biology 2008, 20:508–513
defining feature of the collagen family of proteins [5,6]. In vertebrates, 47 mammalian genes encode collagen a chains and >30 genes encode collagen-like molecules— molecules containing collagenous domains (i.e. Gly-X-Y repeats) but named for other domains or functions (Table 1). Outside of the nervous system, collagens have been extensively studied for their roles as structural molecules and are best known for their ability to assemble into elongated fibers and add tensile strength to tissue. Over the past two decades, however, interest in non-structural activities of collagens has arisen for at least two reasons. Firstly, many recently discovered collagens and collagenlike molecules are not assembled into structural fibers [5,6]. Genes coding for both non-fibril-forming collagens and collagen-like molecules outnumber the 13 fibrilforming collagen genes (Table 1). Secondly, non-collagenous (NC) domains can be proteolytically shed from collagen a chains and can exhibit unconventional bioactivities, unrelated to the structural roles of the collagen from which they were released [7,8]. Thus, collagens are not merely structural molecules but are bio-active adhesion molecules. Non-fibril-forming collagens and collagen-like proteins are widely expressed in both the peripheral and central nervous systems, and are even expressed by neurons (e.g. [9,10–14,15,16–18]). However, their functions in neural development, and specifically in neural circuit formation, have remained relatively unclear. In vitro assays have implicated collagens and collagen-like molecules in contributing to neural cell migration, differentiation, and neurite outgrowth [19,20]. In addition to in vitro assays, invertebrate studies support roles for collagens in neural development: genetic disruption of the NC1/endostatin domain of the C. elegan collagen XVIII homolog, cle-1, causes defects in motor axon guidance and organization of neuromuscular junctions (NMJs)— synapses between motoneurons and muscle fibers [21,22]. Only recently, however, have in vivo roles for collagens and collagen-like molecules been identified in each of the four steps required for vertebrate neural circuit formation.
Axon outgrowth: collagen XVIII and diwanka (lh3) regulate motor axon outgrowth A first step in neural circuit formation is for a neuron to extend an axon in search of a potential synaptic partner. On the basis of its role in C. elegans axon guidance [21] and its expression during periods of motor axon outgrowth [23], collagen XVIII was a promising candidate to regulate www.sciencedirect.com
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Figure 1
zebrafish motor axon outgrowth. Collagen XVIII, encoded by the col18a1 gene in vertebrates, is a heparan sulfate proteoglycan. Proteolytic processing of collagen XVIII releases a non-collagenous bio-active fragment, termed endostatin [6–8]. By blocking col18a1 translation with anti-sense morpholino oligonucleotides, Schneider and Granato recently showed that pioneering motor axons (termed primary motor axons) exit the spinal cord but fail to extend along their normal stereotyped pathways in the absence of collagen XVIII (Figure 2a–c) [24]. Similar to findings seen with col18a1 suppression, axons either fail to exit the spinal cord or stop extending within the common path in another zebrafish mutant, diwanka (Figure 2a, b, and d) [25,26]. Diwanka mutations were recently mapped to the lysyl hydroxylase 3 gene (lh3), which encodes a multifunctional enzyme necessary for post-translationally modifying collagen molecules [5,24,27]. Although other lh genes are highly expressed in embryonic zebrafish muscle, lh3 expression temporally corresponds with motor axon outgrowth and is restricted to col18a1-expressing cells adjacent to the common path [23,24]. On the basis of similar expression patterns and phenotypes, it is tempting to speculate that specific modifications of collagen XVIII by lysyl hydroxylase 3 may influence vertebrate motor axon outgrowth.
Target selection: dragnet (col4a5) is required for layer-specific targeting
Four steps of neural circuit formation.
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As growing axons approach their destination, they must choose an appropriate target. Target selection includes both choosing a specific region to arborize in and a cell to connect with. Synapses between the retina and brain (i.e. either retino-tectal and retino-geniculate synapses) have proved useful for studying target specificity since retinal axons arborize in specific and discrete regions of the tectum or lateral geniculate nucleus (LGN; Figure 2e, f, and k). In zebrafish embryos, growing retinal axons terminate in one of four main retinorecipient tectal layers (Figure 2e and f). Forward genetic screens have identified several putative genes that regulate retino-tectal architecture [28–30]. In one case, Baier and colleagues mutagenized a line of brn3c-GFP transgenic zebrafish, which express GFP in a subset of retinal axons, and identified dragnet, a mutant with mistargeted retinal arbors within the tectal (Figure 2e–h) [30]. Genetic mapping identified the dragnet gene as col4a5—which encodes the a5 chain of collagen IV, a network-forming non-fibrillar collagen [31,32]. Several lines of evidence suggest that dragnet (col4a5) gene activity is required for axon targeting and not outgrowth: Firstly, dragnet axons reach appropriate retinorecipient tectal layers, but sprout promiscuously into inappropriate layers [31]; secondly, injection of collagenase into wild-type tectum after retinal axons arborize within the tectum, phenocopies defects observed in dragnet mutants [31]; thirdly collagen IV does not support retinal axon outgrowth in vitro Current Opinion in Cell Biology 2008, 20:508–513
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Table 1 Collagens and collagen-like molecules Collagen superfamily Fibril-forming collagens Collagen I (col1a1 and col1a2) Collagen II (col2a1) Collagen III (col3a1) Collagen V (col5a1, col5a2, col5a3 and col5a4) Collagen XI (col11a1 and col11a2) Collagen XXIV (col24a1) Collagen XXVII (col27a1)
FACIT and related collagens Collagen IX (col9a1, col9a2 and col9a3) Collagen XII (col12a1) Collagen XIV (col14a1) Collagen XVI (col16a1) Collagen XIX (col19a1) Collagen XX (col20a1) Collagen XXI (col21a1) Collagen XXII (col22a1)
Beaded filament-forming collagens Collagen VI (col6a1, col6a2, col6a3, col6a4, col6a5 and col6a6) Collagen XXVI (col26a1) Emu2 Collagen XXVIII (col28a1) Collagen XXIX (col29a1)
Transmembrane collagens Collagen XIII (col13a1) Collagen XVII (col17a1) Collagen XXIII (col23a1) Collagen XXV (col25a1)
Network-forming collagens Collagen IV (col4a1, col4a2, col4a3, col4a4, col4a5 and col4a6) Collagen VIII (col8a1 and col8a2) C1q Collagen X (col10a1) C1q
Multiplexin collagens Collagen XV (col15a1) Collagen XVIII (col18a1) Anchoring fibril-forming collagen Collagen VII (col7a1)
Collagen-like proteins C1q/TNF superfamily proteins Complement C1q Hibernation proteins (HP20, HP25 and HP27) Emilin 1 Emilin 2 Adiponectin (Acrp30) CORS26 (CTRP3) C1q/TNFa-Related Proteins (CTRP1, CTRP2, CTRP4, CTRP5, CTRP6 and CTRP7) Ectodysplasin A Saccular collagen
Collectins and Ficolins Mannan-binding lectin Surfactant protein-A Surfactant protein-D Collectin-L1 Collectin-P1 Collectin-43 kDa Collectin-46 kDa Conglutinin L-ficolin M-ficolin H-ficolin
Emilin and multimerin 1 (Emu1)
Src-homologous and collagen protein (Shc)
Macrophage receptors Class A scavenger receptors (Types I, II, III) MARCO
Cementum-derived attachment protein Collagenous subunit of acetyl-cholinesterase (colQ) *
Gliomedin Vertebrate collagen molecules are classified by type, designated by roman numerals. Genes coding for a chains contributing to collagen types are italicized in parentheses. Types of collagens are subdivided on the basis of their supramolecular assembly (i.e fibril-forming, beaded filamentforming, network-forming, or anchoring fibril-forming collagens) or their structure and function (i.e. transmembrane collagens, fibril associated collagen with interrupted triple helices [FACIT], or multiplexins) [5,6,42]. In addition to the 47 vertebrate genes that code for collagens, over 30 vertebrate genes code for collagen-like proteins [5,6,43–47]. Several collagens can also be classified with collagen-like proteins: collagen XXVI is also called Emu2 (emilin and multimerin 2) [47,48]; collagen VIII and X contain C1q globular domains (gC1q) and are members of the C1q/TNF superfamily (Kishore et al. 2004). * Unlike other collagen-like molecules, acetylcholinesterase has separate genes that code for either the enzymatic or collagenous subunits [49].
[33]. Thus, dragnet (col4a5) is necessary for targeting and confining retinal axons into appropriate tectal layers. Interestingly col4a5 mRNA is absent from zebrafish tectum, but is expressed in the epidermis covering the tectum [31]. This suggests that non-neural cells assemble a collagen a5(IV)-containing ECM that contributes to the targeting and active confinement of retinal arbors to correct tectal layers. This collagen a5(IV)-rich ECM must therefore be repulsive to some brn3c-positive Current Opinion in Cell Biology 2008, 20:508–513
retinal axons (Figure 2e and g) but attractive to others (Figure 2f and h).
Synaptic differentiation: NC1 domains of collagen IV direct nerve terminal formation and maintenance After contacting appropriate targets, axons and targets must differentiate together into functioning synapses—a process termed synaptic differentiation [1]. Precise www.sciencedirect.com
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Figure 2
coordination of pre- and postsynaptic differentiation suggests that trans-synaptic organizing signals are passed between axon and target. At the NMJ, these trans-synaptic cues are embedded in a specialized basal lamina (BL) lying within the synaptic cleft [34]. Two such extracellular cues, laminin b2 and agrin, are required for pre- and postsynaptic differentiation, respectively [1]. NMJs in mice lacking laminin b2 appear normal at birth but nerve terminals fail to mature perinatally, suggesting other factors contribute to presynaptic differentiation [9,35]. To identify such factors, Sanes and colleagues biochemically fractionated synaptic BL extracts and sought fractions capable of inducing presynaptic differentiation in cultured MNs [9]. One active fraction was identified as the NC1 domain of a collagen IV [9]. Mammalian genomes contain six genes encoding collagen a(IV) chains [32], however, only a2, a3, and a6(IV) NC1 domains exhibit synaptogenic activity in vitro [9]. Of these active a chains, only collagen a2(IV) is present as NMJs form. Motor nerve terminals in mice with reduced levels of a2(IV) have improperly clustered synaptic vesicles and excess nerve terminal sprouts, suggesting a role for a2(IV) in nerve terminal formation in vivo (Figure 2j) [9]. In mice lacking the a3 and a6(IV) chains, which normally appear at synapses postnatally, nerve terminals are improperly maintained [9]. Thus, although all 3 NC1 domains share similar bio-activities in vitro, a2 (IV) chains are necessary for nerve terminal formation and a3 and a6(IV) chains are necessary for actively maintaining nerve terminals in vivo.
Synaptic refinement: C1q refines synaptic connections in the CNS Since an excess of immature synapses initially form in the vertebrate nervous system, appropriate synaptic connections must be maintained while inappropriate connections must be pruned. While the process of synaptic refinement is regulated by neuronal activity [36], the molecular elements regulating this process are not well characterized. Recently, however, Barres and colleagues
Neural phenotypes associated with the loss of vertebrate collagens or collagen-like proteins. (a–d) Collagen XVIII and diwanka are required for motor axon outgrowth. (a) A cross section through a zebrafish embryo demonstrates that three primary motor axons (black, red, and purple) exit the spinal cord (gray) and initially following a similar path, called the common path. Ultimately each axon projects along a unique, stereotyped path within muscle (blue) [50]. (b) Viewed laterally, projections of two primary motor axons are easily observed. (c and d) In embryos with reduced col18a1 (col18a1MO) or mutated lh3 (diwanka), primary motor axons fail to extend beyond the common path. (e–h) Dragnet (col4a5) is required for layer-specific targeting of retino-tectal www.sciencedirect.com
projections. Zebrafish retinal ganglion cell (RGC) axons (black) project from the eye (gray) to one of four layers in the tectum. (e and f) Classes of RGCs expressing Brn3c extend their axons specifically into one of the two tectal layers. (g and h) In the absence of dragnet, Brn3c-positive axons trespass into inappropriate tectal layers. (i and j) Collagen IV is required for mammalian nerve terminal formation. (i) After motor axons (blue) find appropriate target muscle fibers (gray), pre- and postsynaptic differentiation ensues: synaptic vesicles (purple) aggregate in nerve terminals and neurotransmitter receptors (red) cluster in postsynaptic membranes. (j) In mice with reduced levels of collagen IV (col4a1Dex40; see reference [9]), synaptic vesicles fail to properly cluster and sprouts extend beyond the synapse. (k–m) Mammalian retino-geniculate synapse elimination requires C1q. (k) Retinal axons from both eyes (gray) innervate eye-specific domains of each LGN. Blue and lavender indicate regions of each LGN innervated by a given eye. (l) In neonate LGN, retinal inputs from each eye have overlapping arbors (striped region), however, inputs are pruned so that non-overlapping, eye-specific domains are present in the mature LGN. (m) In the absence of C1q, eyespecific segregation is impaired. Current Opinion in Cell Biology 2008, 20:508–513
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revealed a novel role for the collagen-like protein C1q in eliminating inappropriate synapses in the mammalian visual system [15]. Unexpectedly, immature astrocytes induce the expression of C1q, classically an immune molecule, in retinal ganglion cells during normal periods of synaptic refinement [15]. At early postnatal ages in mice, retinal projections from the two eyes are diffusely organized and share terminal space in their target structure, the LGN (Figure 2l) [37]. However, during the first two weeks of life these retinal inputs prune and segregate so the mature LGN has non-overlapping eye-specific domains (Figure 2k and l) [37,38]. In the absence of C1q, this eye-specific segregation is impaired, so that projections remain diffuse and a single LGN cell continues to receive multiple inputs (Figure 2m) [15]. How C1q mediates synaptic refinement in the LGN remains unclear. On the basis of its immunological role in the classical complement cascade [39], C1q might label synapses to be phagocytosed (and thus eliminated) by microglial cells. Whether the collagenous domain of C1q directly contributes to this activity remains unclear, however, it is noteworthy that microglial cells express C1qRp—a receptor that binds the collagenous domain of C1q to enhance phagocytosis [40,41].
Conclusions
4.
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Myllyharju J, Kivirikko KI: Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 2004, 20:33-43.
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Ortega N, Werb Z: New functional roles for non-collagenous domains of basement membrane collagens. J Cell Sci 2002, 115:4201-4214.
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Kalluri R: Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 2003, 3:422-433.
9.
Fox MA, Sanes JR, Borza DB, Eswarakumar VP, Fassler R, Hudson BG, John SW, Ninomiya Y, Pedchenko V, Pfaff SL et al.: Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell 2007, 129:179-193. The authors were the first to demonstrate that NC1 domains of collagen IV influence nerve terminal assembly and maintenance. Moreover, the authors demonstrate that laminin b2 and the FGF7 subfamily also contribute to presynaptic differentiation, and that all three sets of presynaptic organizers act sequentially to form and maintain nerve terminals at the NMJ.
10. Eshed Y, Feinberg K, Poliak S, Sabanay H, Sarig-Nadir O, Spiegel I, Bermingham JR Jr, Peles E: Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron 2005, 47:215-229. The authors identify gliomedin, a Schwann cell-derived collagen-like ligand for neurofascin and NrCAM at peripheral nodes of Ranvier. In vitro experiments demonstrate gliomedin is necessary and sufficient for node formation.
Here, novel roles for collagens and collagen-like molecules in the formation of vertebrate neural circuits have been reviewed [9,15,24,31] The most surprising aspect of the studies reviewed here is the role of collagens in the vertebrate CNS [15,31]. Collagens have long been overlooked for roles in the mammalian brain since neither collagen fibers nor collagen-rich BLs are present in the CNS. However, it is now clear that non-fibril-forming collagens and collagen-like molecules are expressed in the vertebrate CNS, and in some cases are even expressed by neurons. Although the studies highlighted here begin to shed light on potential roles for collagens in the CNS, future studies are needed to identify functions for the many other neural collagens expressed in the vertebrate brain.
11. Claudepierre T, Manglapus MK, Marengi N, Radner S, Champliaud MF, Tasanen K, Bruckner-Tuderman L, Hunter DD, Brunken WJ: Collagen XVII and BPAG1 expression in the retina: evidence for an anchoring complex in the central nervous system. J Comp Neurol 2005, 487:190-203.
Acknowledgements
15. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B et al.: The classical complement cascade mediates CNS synapse elimination. Cell 2007, 131:1164-1178. This study reveals a novel role for complement C1q in synapse elimination in the mammalian CNS. Although neuronal C1q is normally downregulated after periods of synaptic refinement, this study reveals C1q expression is upregulated in early stages of glaucoma. Re-expression of C1q in the adult nervous system may therefore contribute to synaptic (and perhaps neuronal) loss associated with glaucoma.
I am extremely thankful to JW Bigbee, J Dennis, W Guido, and H Umemori for their constructive comments on this manuscript.
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