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Teneurin-1 is expressed in interconnected regions of the developing brain and is processed in vivo.

Kenzelmann D, Chiquet-Ehrismann R, Leachman NT, Tucker RP - BMC Dev. Biol. (2008)

Bottom Line: Moreover we found complementary patterns of teneurin-1 and-2 expression in many parts of the brain, including the retina, optic tectum, olfactory bulb, and cerebellum as well as in brain nuclei involved in processing of sensory information.Finally, the teneurin-1 intracellular domain was found to contain a nuclear localization signal, which is required for nuclear localization in transfected cells.Our data support the hypothesis that teneurins can be proteolytically processed leading to the release of the intracellular domain and its translocation to the nucleus.

View Article: PubMed Central - HTML - PubMed

Affiliation: Friedrich Miescher Institute, Novartis Research Foundation, Maulbeerstr. 66, 4057 Basel, Switzerland. daniela.kenzelmann@fmi.ch

ABSTRACT

Background: Teneurins are a unique family of transmembrane proteins conserved from C. elegans and D. melanogaster to mammals. In vertebrates there are four paralogs (teneurin-1 to -4), all of which are expressed prominently in the developing central nervous system.

Results: Analysis of teneurin-1 expression in the developing chick brain by in situ hybridization and immunohistochemistry defined a unique, distinct expression pattern in interconnected regions of the brain. Moreover we found complementary patterns of teneurin-1 and-2 expression in many parts of the brain, including the retina, optic tectum, olfactory bulb, and cerebellum as well as in brain nuclei involved in processing of sensory information. Based on these expression patterns, we suspect a role for teneurins in neuronal connectivity. In contrast to the cell-surface staining of the antibody against the extracellular domain, an antibody recognizing the intracellular domain revealed nuclear staining in subpopulations of neurons and in undifferentiated mesenchyme. Western blot analysis of brain lysates showed the presence of N-terminal fragments of teneurin-1 containing the intracellular domain indicating that proteolytic processing occurs. Finally, the teneurin-1 intracellular domain was found to contain a nuclear localization signal, which is required for nuclear localization in transfected cells.

Conclusion: Teneurin-1 and -2 are expressed by distinct interconnected populations of neurons in the developing central nervous system. Our data support the hypothesis that teneurins can be proteolytically processed leading to the release of the intracellular domain and its translocation to the nucleus.

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Teneurin-1 is expressed in interconnected regions of the brain and is complementary to teneurin-2 expression. Immunostaining of teneurin-1 and teneurin-2 in E17 brain. Green, teneurin-1; red, teneurin-2, blue (Hoechst), nuclei. In the olfactory bulb (A, B) the teneurin-1 antibody labels the mitral cell layer (mcl) and the glomerular layer. The external plexiform layer (epl) is positive for teneurin-2. In the temporal retina (C, D) subsets of neurons within the ganglion cell layer (gcl) and inner portion of the internal nuclear layer (inl) are positive for teneurin-1, as are laminae 2 and 5 within the inner plexiform layer (ipl). Teneurin-2 immunoreactivity is concentrated in laminae 1 and 3 of the ipl. The nucleus rotundus (E, ROT) is intensely labelled with teneurin-1 antibody, but not with anti-teneurin-2 (F). In the optic tectum (G, H) large neurons in the stratum griseum centrale (SGC) are positive for teneurin-1, but not teneurin-2. In the hindbrain (I, J), the nucleus laminaris (La) and nucleus magnocellularis (MCC) are labelled with the teneurin-1 antibody. Teneurin-1 and teneurin-2 immunoreactivity are found in distinctive dendritic fields within the La. In the cerebellum (K, L) teneurin-1 is found in Purkinje cells (Pcl) and in the molecular layer (ml) adjacent to the external granular layer (egl). In contrast, the anti-teneurin-2 labels the internal portion of the ml.
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Figure 2: Teneurin-1 is expressed in interconnected regions of the brain and is complementary to teneurin-2 expression. Immunostaining of teneurin-1 and teneurin-2 in E17 brain. Green, teneurin-1; red, teneurin-2, blue (Hoechst), nuclei. In the olfactory bulb (A, B) the teneurin-1 antibody labels the mitral cell layer (mcl) and the glomerular layer. The external plexiform layer (epl) is positive for teneurin-2. In the temporal retina (C, D) subsets of neurons within the ganglion cell layer (gcl) and inner portion of the internal nuclear layer (inl) are positive for teneurin-1, as are laminae 2 and 5 within the inner plexiform layer (ipl). Teneurin-2 immunoreactivity is concentrated in laminae 1 and 3 of the ipl. The nucleus rotundus (E, ROT) is intensely labelled with teneurin-1 antibody, but not with anti-teneurin-2 (F). In the optic tectum (G, H) large neurons in the stratum griseum centrale (SGC) are positive for teneurin-1, but not teneurin-2. In the hindbrain (I, J), the nucleus laminaris (La) and nucleus magnocellularis (MCC) are labelled with the teneurin-1 antibody. Teneurin-1 and teneurin-2 immunoreactivity are found in distinctive dendritic fields within the La. In the cerebellum (K, L) teneurin-1 is found in Purkinje cells (Pcl) and in the molecular layer (ml) adjacent to the external granular layer (egl). In contrast, the anti-teneurin-2 labels the internal portion of the ml.

Mentions: Polyclonal antibodies raised against recombinant fragments of teneurin-1 were used to study the distribution of teneurin-1 protein in the developing avian nervous system. Our results are summarized in Figure 2 and are briefly described here starting in the rostral forebrain and ending in the hindbrain, emphasizing regions also illustrated in Figure 1. At E17 the anti-teneurin-1 serum labelled the glomerular layer and mitral cell layer of the olfactory bulb (Fig. 2A). This pattern is consistent with the expression of teneurin-1 by mitral cells shown in Figure 1A and the transportation of the protein to the dendrites of mitral cells in the glomerular layer. In the retina teneurin-1 immunolabelling was observed in retinal ganglion cells, neurons within the inner nuclear layer adjacent to the inner plexiform layer, and within distinctive laminae (especially 2 and 5) within the inner plexiform layer (Fig. 2C). As predicted by in situ hybridization, teneurin-1 immunoreactivity was particularly strong throughout the rotund nucleus (Fig. 2E) and in the large neurons of the stratum griseum centrale of the optic tectum (Fig. 2G), two interconnected populations of neurons that make up part of the tectofugal visual pathway. Finally, the anti-teneurin-1 labelled the dendritic field of the external portion of the nucleus laminaris (Fig. 2I), the large neurons of the nucleus magnocellularis (Fig. 2I), and in the cerebellum labelled Purkinje cells and the portion of the molecular layer adjacent to the external granular layer (Fig. 2K). Note that the teneurin-1 expression pattern observed with the antibody is more extensive in most brain regions than observed by in situ hybridization. For example, neurons in the outer portion of the inner nuclear layer of the E17 retina are stained with the antibody (Fig. 2C), but are not positive for teneurin-1 transcripts (Fig. 1B). Since these cells were not stained with preimmune serum or secondary antibody only controls (not shown), a possible explanation for this discrepancy is that teneurin-1 transcripts are present below the level of detection of our in situ hybridization protocol in some regions, but nevertheless at levels sufficient to generate enough protein to be recognized, albeit faintly, by immunohistochemistry.


Teneurin-1 is expressed in interconnected regions of the developing brain and is processed in vivo.

Kenzelmann D, Chiquet-Ehrismann R, Leachman NT, Tucker RP - BMC Dev. Biol. (2008)

Teneurin-1 is expressed in interconnected regions of the brain and is complementary to teneurin-2 expression. Immunostaining of teneurin-1 and teneurin-2 in E17 brain. Green, teneurin-1; red, teneurin-2, blue (Hoechst), nuclei. In the olfactory bulb (A, B) the teneurin-1 antibody labels the mitral cell layer (mcl) and the glomerular layer. The external plexiform layer (epl) is positive for teneurin-2. In the temporal retina (C, D) subsets of neurons within the ganglion cell layer (gcl) and inner portion of the internal nuclear layer (inl) are positive for teneurin-1, as are laminae 2 and 5 within the inner plexiform layer (ipl). Teneurin-2 immunoreactivity is concentrated in laminae 1 and 3 of the ipl. The nucleus rotundus (E, ROT) is intensely labelled with teneurin-1 antibody, but not with anti-teneurin-2 (F). In the optic tectum (G, H) large neurons in the stratum griseum centrale (SGC) are positive for teneurin-1, but not teneurin-2. In the hindbrain (I, J), the nucleus laminaris (La) and nucleus magnocellularis (MCC) are labelled with the teneurin-1 antibody. Teneurin-1 and teneurin-2 immunoreactivity are found in distinctive dendritic fields within the La. In the cerebellum (K, L) teneurin-1 is found in Purkinje cells (Pcl) and in the molecular layer (ml) adjacent to the external granular layer (egl). In contrast, the anti-teneurin-2 labels the internal portion of the ml.
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Figure 2: Teneurin-1 is expressed in interconnected regions of the brain and is complementary to teneurin-2 expression. Immunostaining of teneurin-1 and teneurin-2 in E17 brain. Green, teneurin-1; red, teneurin-2, blue (Hoechst), nuclei. In the olfactory bulb (A, B) the teneurin-1 antibody labels the mitral cell layer (mcl) and the glomerular layer. The external plexiform layer (epl) is positive for teneurin-2. In the temporal retina (C, D) subsets of neurons within the ganglion cell layer (gcl) and inner portion of the internal nuclear layer (inl) are positive for teneurin-1, as are laminae 2 and 5 within the inner plexiform layer (ipl). Teneurin-2 immunoreactivity is concentrated in laminae 1 and 3 of the ipl. The nucleus rotundus (E, ROT) is intensely labelled with teneurin-1 antibody, but not with anti-teneurin-2 (F). In the optic tectum (G, H) large neurons in the stratum griseum centrale (SGC) are positive for teneurin-1, but not teneurin-2. In the hindbrain (I, J), the nucleus laminaris (La) and nucleus magnocellularis (MCC) are labelled with the teneurin-1 antibody. Teneurin-1 and teneurin-2 immunoreactivity are found in distinctive dendritic fields within the La. In the cerebellum (K, L) teneurin-1 is found in Purkinje cells (Pcl) and in the molecular layer (ml) adjacent to the external granular layer (egl). In contrast, the anti-teneurin-2 labels the internal portion of the ml.
Mentions: Polyclonal antibodies raised against recombinant fragments of teneurin-1 were used to study the distribution of teneurin-1 protein in the developing avian nervous system. Our results are summarized in Figure 2 and are briefly described here starting in the rostral forebrain and ending in the hindbrain, emphasizing regions also illustrated in Figure 1. At E17 the anti-teneurin-1 serum labelled the glomerular layer and mitral cell layer of the olfactory bulb (Fig. 2A). This pattern is consistent with the expression of teneurin-1 by mitral cells shown in Figure 1A and the transportation of the protein to the dendrites of mitral cells in the glomerular layer. In the retina teneurin-1 immunolabelling was observed in retinal ganglion cells, neurons within the inner nuclear layer adjacent to the inner plexiform layer, and within distinctive laminae (especially 2 and 5) within the inner plexiform layer (Fig. 2C). As predicted by in situ hybridization, teneurin-1 immunoreactivity was particularly strong throughout the rotund nucleus (Fig. 2E) and in the large neurons of the stratum griseum centrale of the optic tectum (Fig. 2G), two interconnected populations of neurons that make up part of the tectofugal visual pathway. Finally, the anti-teneurin-1 labelled the dendritic field of the external portion of the nucleus laminaris (Fig. 2I), the large neurons of the nucleus magnocellularis (Fig. 2I), and in the cerebellum labelled Purkinje cells and the portion of the molecular layer adjacent to the external granular layer (Fig. 2K). Note that the teneurin-1 expression pattern observed with the antibody is more extensive in most brain regions than observed by in situ hybridization. For example, neurons in the outer portion of the inner nuclear layer of the E17 retina are stained with the antibody (Fig. 2C), but are not positive for teneurin-1 transcripts (Fig. 1B). Since these cells were not stained with preimmune serum or secondary antibody only controls (not shown), a possible explanation for this discrepancy is that teneurin-1 transcripts are present below the level of detection of our in situ hybridization protocol in some regions, but nevertheless at levels sufficient to generate enough protein to be recognized, albeit faintly, by immunohistochemistry.

Bottom Line: Moreover we found complementary patterns of teneurin-1 and-2 expression in many parts of the brain, including the retina, optic tectum, olfactory bulb, and cerebellum as well as in brain nuclei involved in processing of sensory information.Finally, the teneurin-1 intracellular domain was found to contain a nuclear localization signal, which is required for nuclear localization in transfected cells.Our data support the hypothesis that teneurins can be proteolytically processed leading to the release of the intracellular domain and its translocation to the nucleus.

View Article: PubMed Central - HTML - PubMed

Affiliation: Friedrich Miescher Institute, Novartis Research Foundation, Maulbeerstr. 66, 4057 Basel, Switzerland. daniela.kenzelmann@fmi.ch

ABSTRACT

Background: Teneurins are a unique family of transmembrane proteins conserved from C. elegans and D. melanogaster to mammals. In vertebrates there are four paralogs (teneurin-1 to -4), all of which are expressed prominently in the developing central nervous system.

Results: Analysis of teneurin-1 expression in the developing chick brain by in situ hybridization and immunohistochemistry defined a unique, distinct expression pattern in interconnected regions of the brain. Moreover we found complementary patterns of teneurin-1 and-2 expression in many parts of the brain, including the retina, optic tectum, olfactory bulb, and cerebellum as well as in brain nuclei involved in processing of sensory information. Based on these expression patterns, we suspect a role for teneurins in neuronal connectivity. In contrast to the cell-surface staining of the antibody against the extracellular domain, an antibody recognizing the intracellular domain revealed nuclear staining in subpopulations of neurons and in undifferentiated mesenchyme. Western blot analysis of brain lysates showed the presence of N-terminal fragments of teneurin-1 containing the intracellular domain indicating that proteolytic processing occurs. Finally, the teneurin-1 intracellular domain was found to contain a nuclear localization signal, which is required for nuclear localization in transfected cells.

Conclusion: Teneurin-1 and -2 are expressed by distinct interconnected populations of neurons in the developing central nervous system. Our data support the hypothesis that teneurins can be proteolytically processed leading to the release of the intracellular domain and its translocation to the nucleus.

Show MeSH
Related in: MedlinePlus