1 Friedrich Miescher Institute, Novartis Research Foundation, PO Box 2543, CH-4002 Basel, Switzerland
2 Department of Cell Biology and Human Anatomy, University of California at Davis, Davis, CA 95616, USA
* These authors contributed equally to this work
Author for correspondence (e-mail: chiquet{at}fmi.ch)
Accepted 20 June 2002
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SUMMARY |
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Key words: DOC4, Neurestin, Odz, Tenm, Tena, Ten-m, Chicken
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INTRODUCTION |
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The domain organization of teneurins in invertebrates and vertebrates is highly conserved. All teneurins have a proline-rich cytoplasmic domain, and extracellularly contain a series of EGF-like repeats and 26 YD repeats (Minet and Chiquet-Ehrismann, 2000). The cytoplasmic domain may be involved in a signal transduction cascade, as mutational analysis showed that ten-m/odz is a member of the pair-rule gene family and has a central role in determining the segmentation of the Drosophila embryo (Baumgartner et al., 1994
). A highly conserved dibasic furin-like cleavage site is found between the transmembrane domain and the EGF-like repeats (Rubin et al., 1999
), meaning that teneurins may be proteolytically processed in the same way as Notch (Logeat et al., 1998
). The function of the EGF-like repeats is unknown, but a recombinant murine teneurin forms side-by-side dimers in vitro that appear to be linked via disulfide bridges between the EGF-like repeats (Oohashi et al., 1999
). The YD repeats bind heparin (Minet et al., 1999
) and are similar to those found in the rhs element of E. coli and in wall associated protein A of Bacillus subtilis, where they may have appeared due to horizontal gene transfer from an ancestral teneurin (Minet and Chiquet-Ehrismann, 2000
).
Unlike Drosophila, which has two teneurin genes, vertebrates have up to four teneurin genes (Minet and Chiquet-Ehrismann, 2000; Oohashi et al., 1999
). Although different nomenclatures have been developed in laboratories using different animal models, the number designation at the end of each name can be used to identify the orthologous genes: murine ten-m1 (Oohashi et al., 1999
) is the same as murine odz1 (Ben-Zur et al., 2000
) and corresponds to avian teneurin 1 (Rubin et al., 1999
), etc. Note that the murine Doc4 gene (Wang et al., 1998
) encodes ten-m4 (Oohashi et al., 1999
), and that the rat teneurin 2 ortholog has also been called neurestin (Otaki and Firestein, 1999b
). In addition, at least three alternatively spliced variants of teneurin 2 have been identified (Tucker et al., 2001
), including one variant that lacks the YD repeats. The functional significance of these variations is unknown.
There is some experimental evidence that teneurins may play a role in neurite outgrowth and pathfinding. In vitro, the YD repeats of teneurin 2 support the outgrowth of neurites, and this outgrowth is abolished by heparin (Minet et al., 1999). Transfection of Nb2a neuroblastoma cells with chicken teneurin 2 expression constructs results in the formation of numerous teneurin 2-enriched filopodia and enlarged growth cones, suggesting an interaction of teneurin 2 with the cytoskeleton (Rubin et al., 1999
). In situ hybridization reveals non-overlapping neuronal expression of teneurin 1 and teneurin 2 in interconnected parts of the developing diencephalon and midbrain (Rubin et al., 1999
). The possibility of homophilic interactions between these teneurins is supported by the observations of Oohashi et al. (Oohashi et al., 1999
) that labeled ten-m1 binds to ten-m1 on blots, and labeled ten-m1 binds to ten-m1-rich regions of tissue sections. Finally, the human teneurin 1 gene maps to the same part of the X-chromosome (Xq25) as an X-linked mental retardation syndrome characterized by sensory neuropathology (Minet et al., 1999
).
We show by immunohistochemistry that teneurin 2 is expressed in specific brain regions by neurons that are known to be part of a specific circuit, namely the thalamofugal visual system of the chicken. Teneurin 2 is expressed at the time when axons find their targets. Furthermore, functional tests prove teneurin 2 to be a homophilic cell-adhesion protein fitting the hypothesis that teneurin 2 provides neurons with the capability of recognizing and forming synapses with other teneurin 2-expressing neurons.
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MATERIALS AND METHODS |
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Whole-mount in situ hybridization was carried out on E10 brains using methods described elsewhere (Tucker et al., 2001; Wilkinson and Nieto, 1993
). In brief, whole brains were dissected from E10 chicken heads after fixation in 4% paraformaldehyde, cut sagittally at the midline, then dehydrated in methanol and stored at 20°C. Hybridization with a digoxigenin-labeled RNA probe to teneurin 2 (ten-2L) (Tucker et al., 2001
) or a sense control probe was followed by extensive rinses and incubation for 40 hours at 4°C in TBST/1% goat serum with alkaline phosphatase-tagged anti-digoxigenin (Boehringer Mannheim) diluted 1:1000. NBT/BCIP was used for the color reaction. Frozen sections (see above) through retinas at E12 and whole brains at E18 were processed similarly to localize teneurin 2 transcripts in cells.
Teneurin 2 constructs and transfection of cells
Four different teneurin 2 constructs were used in the present study. All of them are cloned in pcDNA3/Neo (Invitrogen). They are named according to the protein domains contained within their coding regions (see Fig. 3). Construct CTE has been used previously (Rubin et al., 1999) and contains the complete coding region of a short splice variant of teneurin 2 (Accession Number, AJ245711). Construct CTEY contains the complete coding region of the long form of teneurin 2 described elsewhere (Tucker et al., 2001
) (Accession Number, AJ279031). Constructs TEY and TE are derived from each of the above constructs, respectively, by deletion of amino acids 1-362 of the cytoplasmic domain. The plasmids were either transfected into COS-7 or Nb2a neuroblastoma cells for transient expression studies or into HT1080 cells to isolate stably expressing clones using the transfection reagent fugene (Roche Diagnostics). After transfection, HT1080 cells were plated at low enough dilution to result in clonal growth of transfected cells. Several clones representing each construct were picked and screened for recombinant protein expression by immunofluorescence as well as by immunoblotting. Phalloidin staining and detection of the recombinantly expressed teneurin 2 proteins with the teneurin 2 antibody by immunocytochemistry was done as described previously (Rubin et al., 1999
). Teneurin 2-containing cellular extracts for immunoblotting were prepared as follows. After washing the cells on 5 cm culture dishes with cold PBS, plates were frozen at 20°C. After thawing, they were extracted for 30 minutes on ice with 600 µl of hypotonic buffer [20 mM KCl, 2 mM sodium phosphate (pH 7.0), 1 mM ß-mercaptoethanol]. Cells were collected by scraping with a rubber policeman and transferred into Eppendorf tubes. After spinning for 10 minutes at maximum speed the pellet was dissolved at 37°C for 20 minutes in 60 µl detergent buffer [150 mM NaCl, 50 mM Tris (pH 8), 1% NP-40, 6 M urea, 5 mM EDTA] per plate. An equal volume of SDS-PAGE sample buffer [0.2 M Tris-HCl (pH 6.8) 4% SDS, 17.4% glycerol/20% ß-mercaptoethanol, 6 M urea] was added and the sample was incubated for 1 hour at 52°C. The samples were separated on SDS-PAGE and transferred to PVDF membranes. The teneurins were detected by the anti-teneurin 2 serum (Rubin et al., 1999
) and the signals revealed using the ECL system (Amersham).
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Cos7 cells were co-transfected with the ten-2 construct CTEY and a plasmid encoding EGFP under the control of a ß-actin promoter (kindly provided by Andrew Matus, Friedrich Miescher Institute) using the transfection reagent fugene (Roche Diagnostics). The transfected cells were cultured for 24 hours before harvesting them as described for the HT1080 cells. Aggregation assays were performed as with the HT1080 cells. After 3 hours, pictures of the aggregates were taken using a Zeiss Axiophot microscope (Carl Zeiss).
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RESULTS |
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In vitro expression of teneurin 2 constructs
The timing and distribution of teneurin 2 expression in the developing nervous system implied a possible function of teneurin 2 in neurite fasciculation and/or neuron target recognition. We decided to test this hypothesis on the cellular level by expressing teneurin 2 recombinantly in cell cultures. First we expressed four different membrane-anchored teneurin 2 constructs in COS-7 cells: CTEY (for cytoplasmic, transmembrane, EGF-like and YD-repeats), containing the cytoplasmic domain as well as the entire long form of the extracellular domain; TEY, the same with a deleted cytoplasmic domain; CTE, corresponding to a short splice variant of teneurin 2 (Rubin et al., 1999); or TE, the same but without a cytoplasmic domain (Fig. 3A). Cell extracts were prepared 24 hours after transfection and analyzed by SDS-PAGE and immunoblotting with anti-teneurin 2 serum. Each construct resulted in the presence of a major band of roughly the expected size. The proteins without the cytoplasmic tails (TEY and TE) always had an Mr of
40x103, which is smaller than the corresponding proteins with these domains present (CTEY and CTE) (Fig. 3B). Immunostaining of the transfected cells without permeabilization prior to antiserum incubation revealed the presence of the extracellular domains of teneurin 2 on the cell surface. Interestingly, the morphology of the cells expressing the constructs including the cytoplasmic domains was very different from the ones without the cytoplasmic domain (Fig. 3C). Whereas CTEY and CTE induced prominent filopodia in the transfected cells, TEY and TE was present in cells with smooth surfaces. This implies an interaction of the teneurin 2 cytoplasmic domain with yet-to-be identified cytoskeletal components.
Expression of the extracellular domain of teneurin 2 leads to cell aggregation
Next we tried to isolate stable cell lines expressing these four types of teneurin 2 proteins. HT1080 cells were transfected and replated at high enough dilution to allow clonal growth of the transfected cells. We selected several clones of two constructs, TEY and TE, that lack the cytoplasmic domain (Fig. 3B; Fig. 4). However, several attempts to obtain clones from constructs CTEY or CTE (containing the cytoplasmic domain) were unsuccessful. It appears that the presence of the cytoplasmic domain is not tolerated very well by the cells and interferes with their ability to survive or proliferate. A comparison between the morphology of the parental cell line and examples of several clones are shown in Fig. 4. We consistently noticed that all clones expressing the long form of the extracellular domain (TEY1, TEY2, TEY3) showed a much flatter morphology than either the parental cells (HT1080) or the cells expressing the short teneurin extracellular domain (TE1) as can be seen both on the phase contrast pictures (Fig. 4A), as well as after phalloidin staining of the actin cytoskeleton (Fig. 4B). Despite their flat morphology the clones, TEY1, TEY2 and TEY3 did not contain a more pronounced actin cytoskeleton than the parental cells and all cells revealed mostly cortical actin staining.
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The cytoplasmic domain of teneurin 2 is required for transport into neurites
We further investigated the effect of the expression of the teneurin 2 constructs on Nb2a neuroblastoma cells. As previously reported (Rubin et al., 1999), expression of CTE constructs in Nb2a cells led to the induction of filopodia and enlarged growth cones (Fig. 6A,B). This effect was not seen after transfection of the TE construct (lacking the cytoplasmic domain). In addition, the TE protein mainly localized to the plasma membrane of cell bodies and not to neurites (Fig. 6C,D). This suggests that the cytoplasmic domain is required for the translocation of teneurin protein to neurites and growth cones in addition to the induction of filopodia. The transfection of the longer constructs CTEY and TEY resulted in quite different teneurin 2 expression patterns. Both of these proteins were expressed on the cell surfaces and were heavily enriched in cell-cell contact areas, giving further support for the promotion of homophilic interactions between these neuronal cells (Fig. 6E-H). Interestingly, the CTEY expression led to the accumulation of actin to these teneurin-rich cell-cell contacts as revealed by phalloidin staining (Fig. 6F), which was not the case for the TEY construct (Fig. 6H). This provides evidence for an interaction between teneurin 2 and the actin cytoskeleton through its cytoplasmic domain.
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DISCUSSION |
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The visual system is commonly used as a model to test Sperrys hypothesis. In the avian visual system there are two principal circuits: the tectofugal pathway and the thalamofugal pathway (Fig. 7A). In the tectofugal pathway, retinal ganglion cells project to the optic tectum where they synapse in an ordered fashion to create a map of the visual field. Neurons within the optic tectum, in turn, project to the rotund nucleus of the diencephalon, which then projects to the ectostriatum of the telencephalon. This pathway is responsible for color discrimination, brightness, acuity and other crucial visual functions (for reviews, see Mey and Thanos, 2000; Shimizu and Bowers, 1999
). The retina also sends processes to visual centers in the dorsal thalamus. These in turn project to the visual Wulst, which then projects back to the mesencephalon, including the optic tectum. This latter circuit is the thalamofugal pathway, which is believed to play a role in modulating the tectofugal pathway and in the detection of movements (reviewed by Mey and Thanos, 2000
).
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Although the principal sites of teneurin 2 expression were parts of the thalamofugal visual pathway, teneurin 2 was found in a few other parts of the embryonic CNS as well. The most prominent of these were the expression seen in Hp, the SN and nucleus taenia. Although not considered part of the thalamofugal visual pathway, these interconnected regions are speculated to play a role in spatial memory and pattern recognition (Colombo et al., 2001). Another interesting site of expression is the IO, which sends processes back along the teneurin 2-positive optic tract to the retina (Von Bartheld and Johnson, 2001
). Both the Hp and the IO project to regions that also expressed teneurin 2, supporting the hypothesis that teneurin 2/teneurin 2 interactions may play a role in the development of appropriate synapses. Finally, two other regions that were positive for teneurin 2 expression at E18, the olfactory bulb [see also the observations made by Otaki and Firestein (Otaki and Firestein, 1999a
; Otaki and Firestein, 1999b
)] and cerebellum, are connected to the teneurin 2-positive regions of the developing visual system. The latter receives fibers from the visual Wulst (Wild and Williams, 2000
), and the former receives fibers from a part of the hypothalamus that: (1) is a target of retinal projections (Ehrlich and Mark, 1984
) and (2) also projects to the visual Wulst and Hp (Ehrlich and Mark, 1984
).
Other protein-protein interaction systems have been shown to insure proper wiring of the brain. A prominent example was discovered through the cloning of the mutated gene in the reeler mouse. In this mouse line, neurons fail to reach their correct locations in the developing brain, leading to a disruption of the laminar organization of the cerebellar and cerebral cortices. The affected gene product, reelin, is a large secreted extracellular matrix protein (DArcangelo et al., 1995). There is evidence for several types of reelin receptors present on neurons, namely protocadherins (Senzaki et al., 1999
), the VLDL-receptor and ApoE receptor 2 (Hiesberger et al., 1999
), and integrin
3ß1 (Dulabon et al., 2000
), all of which are though to be part of a reelin signaling pathway. Reelin and its signaling pathway through disabled 1 are also important in the development of the visual system, as mice deficient in reelin or disabled 1 show disturbed patterns of synaptic connections in the retina (Rice et al., 2001
). The exact mechanism of reelin action is still unclear and a direct effect on axon growth has recently been questioned (Jossin and Goffinet, 2001
). At least part of its action could be due to its recently discovered role as a serine protease that is able to degrade the integrin ligands fibronectin and laminin (Quattrocchi et al., 2002
).
Protocadherins (Wu and Maniatis, 1999) and the classical cadherins are also well recognized candidates for cell-surface recognition proteins delineating and determining neural circuits. Experimental evidence suggests that cadherins contribute to central nervous system regionalization, morphogenesis and fiber tract formation, probably be conferring homotypic adhesiveness between neurons (for reviews, see Shapiro and Colman, 1999
; Ranscht, 2000
; Redies, 2000
; Hamada and Yagi, 2001
). Genetic evidence in Drosophila clearly demonstrates a role for N-cadherin in target finding in the visual system (Lee et al., 2001
; Chiba, 2001
). In humans, mutations in specific protocadherin genes cause sensorineural deafness and vestibular dysfunction as well as visual impairment due to retinitis pigmentosa (Bolz et al., 2001
; Bork et al., 2001
; Ahmed et al., 2001
; Petit, 2001
). In addition to the cadherins, protein-protein interactions between ephrins and Eph-recepters (Braisted et al., 1997
; Castellani et al., 1998
) or neuroligin and neurexin are also important factors determining synaptogenesis in the central nervous system (Cantallops and Cline, 2000
).
Using specific constructs, we have begun to dissect the domains of teneurin 2 to understand the functions of its different domains. The cytoplasmic domain is responsible for transportation of teneurin 2 into cellular processes and its association with the actin cytoskeleton. This domain is also responsible for the induction of filopodia and may also play a role in regulating cell growth and proliferation. Future studies should be directed to identifying the binding partners of this domain. Others have suggested that the EGF-like repeats are involved in the side-by-side dimerization of teneurins (Oohashi et al., 1999), and our results demonstrate that these domains alone do not play a role in the homophilic interactions that lead to the aggregation of cells in vitro. This activity depends instead on the part of the molecule distal to the EGF-like repeats. This part of teneurin 2 also plays a role in regulating cell spreading in vitro. Thus, through a combination of morphological and experimental methods, we have shown that teneurin 2 is expressed at the right time and place, and has the appropriate properties in vitro to be a molecular specifier that regulates the development of appropriate synapses in the avian visual system.
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ACKNOWLEDGMENTS |
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