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Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction.

Yumoto N, Wakatsuki S, Kurisaki T, Hara Y, Osumi N, Frisén J, Sehara-Fujisawa A - PLoS ONE (2008)

Bottom Line: Meltrin beta plays a regulatory role in formation of the NMJ.The endocytosis of ephrin-Eph complexes is required for efficient contact-dependent repulsion between ephrin and Eph.We propose that Meltrin beta stabilizes the interaction between ephrin-A5 and EphA4 by regulating endocytosis of the ephrinA5-EphA complex negatively, which would contribute to the fine-tuning of the NMJ during development.

View Article: PubMed Central - PubMed

Affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Shogo-in, Kyoto, Japan.

ABSTRACT

Background: Development of the neuromuscular junction (NMJ) is initiated by the formation of postsynaptic specializations in the central zones of muscles, followed by the arrival of motor nerve terminals opposite the postsynaptic regions. The post- and presynaptic components are then stabilized and modified to form mature synapses. Roles of ADAM (A Disintegrin And Metalloprotease) family proteins in the formation of the NMJ have not been reported previously.

Principal findings: We report here that Meltrin beta, ADAM19, participates in the formation of the NMJ. The zone of acetylcholine receptor alpha mRNA distribution was broader and excess sprouting of motor nerve terminals was more prominent in meltrin beta-deficient than in wild-type embryonic diaphragms. A microarray analysis revealed that the preferential distribution of ephrin-A5 mRNA in the synaptic region of muscles was aberrant in the meltrin beta-deficient muscles. Excess sprouting of motor nerve terminals was also found in ephrin-A5 knockout mice, which lead us to investigate a possible link between Meltrin beta and ephrin-A5-Eph signaling in the development of the NMJ. Meltrin beta and EphA4 interacted with each other in developing motor neurons, and both of these proteins localized in the NMJ. Coexpression of Meltrin beta and EphA4 strongly blocked vesicular internalization of ephrin-A5-EphA4 complexes without requiring the protease activity of Meltrin beta, suggesting a regulatory role of Meltrin beta in ephrin-A5-Eph signaling.

Conclusion: Meltrin beta plays a regulatory role in formation of the NMJ. The endocytosis of ephrin-Eph complexes is required for efficient contact-dependent repulsion between ephrin and Eph. We propose that Meltrin beta stabilizes the interaction between ephrin-A5 and EphA4 by regulating endocytosis of the ephrinA5-EphA complex negatively, which would contribute to the fine-tuning of the NMJ during development.

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Hypothetic model of how Meltrin β and ephrin-A5–EphA4 signaling stabilize the NMJ.When axon terminals touch the ephrin-A5-expressing postsynaptic region, EphA4 associated with Meltrin β is localized preferentially at the axon terminal opposite the postsynaptic cluster on the muscle fiber; Meltrin β interferes with the internalization of the ephrin-A5–EphA4 complexes so that the axon terminal and muscle could avoid receiving a repulsive signal at the NMJ, and many molecules, such as agrin, MuSK and adhesion proteins, cooperate in stabilization of the NMJ. In the absence of Meltrin β, axon terminals of motor neurons cannot be stabilized because impaired suppression of endocytosis would result in a failure to block the ephrin-A5–EphA4 repulsive signal. As a result, the motor terminals remain mobile at the NMJ, and the reverse signal from EphA4 to ephrin-A5 is unstable, leading to the diffuse distribution of ephrin-A5 and AChR transcripts in muscles. (see also text).
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pone-0003322-g007: Hypothetic model of how Meltrin β and ephrin-A5–EphA4 signaling stabilize the NMJ.When axon terminals touch the ephrin-A5-expressing postsynaptic region, EphA4 associated with Meltrin β is localized preferentially at the axon terminal opposite the postsynaptic cluster on the muscle fiber; Meltrin β interferes with the internalization of the ephrin-A5–EphA4 complexes so that the axon terminal and muscle could avoid receiving a repulsive signal at the NMJ, and many molecules, such as agrin, MuSK and adhesion proteins, cooperate in stabilization of the NMJ. In the absence of Meltrin β, axon terminals of motor neurons cannot be stabilized because impaired suppression of endocytosis would result in a failure to block the ephrin-A5–EphA4 repulsive signal. As a result, the motor terminals remain mobile at the NMJ, and the reverse signal from EphA4 to ephrin-A5 is unstable, leading to the diffuse distribution of ephrin-A5 and AChR transcripts in muscles. (see also text).

Mentions: On the basis of our findings and previous reports, we present a working hypothesis of how Meltrin β and ephrin-A5–EphA signaling cooperate to stabilize the association of the pre- and postsynaptic apparatuses of the NMJ (Fig. 7). In short, Meltrin β associated with EphA4 would convert a state of an axon terminal from a mobile to a static one through modulating the ephrinA5-EphA4 signaling at the NMJ by interfering with the internalization of the ephrin-Eph complexes there. This conversion might contribute to formation of the stabilized NMJ. The sustained expression of EphA4-Meltrin β at the presynapses would cause localized expression of ephrin-A5 at the postsynapses, which would increase the stability of the ephrin-A5-EphA4 interaction.


Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction.

Yumoto N, Wakatsuki S, Kurisaki T, Hara Y, Osumi N, Frisén J, Sehara-Fujisawa A - PLoS ONE (2008)

Hypothetic model of how Meltrin β and ephrin-A5–EphA4 signaling stabilize the NMJ.When axon terminals touch the ephrin-A5-expressing postsynaptic region, EphA4 associated with Meltrin β is localized preferentially at the axon terminal opposite the postsynaptic cluster on the muscle fiber; Meltrin β interferes with the internalization of the ephrin-A5–EphA4 complexes so that the axon terminal and muscle could avoid receiving a repulsive signal at the NMJ, and many molecules, such as agrin, MuSK and adhesion proteins, cooperate in stabilization of the NMJ. In the absence of Meltrin β, axon terminals of motor neurons cannot be stabilized because impaired suppression of endocytosis would result in a failure to block the ephrin-A5–EphA4 repulsive signal. As a result, the motor terminals remain mobile at the NMJ, and the reverse signal from EphA4 to ephrin-A5 is unstable, leading to the diffuse distribution of ephrin-A5 and AChR transcripts in muscles. (see also text).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2552171&req=5

pone-0003322-g007: Hypothetic model of how Meltrin β and ephrin-A5–EphA4 signaling stabilize the NMJ.When axon terminals touch the ephrin-A5-expressing postsynaptic region, EphA4 associated with Meltrin β is localized preferentially at the axon terminal opposite the postsynaptic cluster on the muscle fiber; Meltrin β interferes with the internalization of the ephrin-A5–EphA4 complexes so that the axon terminal and muscle could avoid receiving a repulsive signal at the NMJ, and many molecules, such as agrin, MuSK and adhesion proteins, cooperate in stabilization of the NMJ. In the absence of Meltrin β, axon terminals of motor neurons cannot be stabilized because impaired suppression of endocytosis would result in a failure to block the ephrin-A5–EphA4 repulsive signal. As a result, the motor terminals remain mobile at the NMJ, and the reverse signal from EphA4 to ephrin-A5 is unstable, leading to the diffuse distribution of ephrin-A5 and AChR transcripts in muscles. (see also text).
Mentions: On the basis of our findings and previous reports, we present a working hypothesis of how Meltrin β and ephrin-A5–EphA signaling cooperate to stabilize the association of the pre- and postsynaptic apparatuses of the NMJ (Fig. 7). In short, Meltrin β associated with EphA4 would convert a state of an axon terminal from a mobile to a static one through modulating the ephrinA5-EphA4 signaling at the NMJ by interfering with the internalization of the ephrin-Eph complexes there. This conversion might contribute to formation of the stabilized NMJ. The sustained expression of EphA4-Meltrin β at the presynapses would cause localized expression of ephrin-A5 at the postsynapses, which would increase the stability of the ephrin-A5-EphA4 interaction.

Bottom Line: Meltrin beta plays a regulatory role in formation of the NMJ.The endocytosis of ephrin-Eph complexes is required for efficient contact-dependent repulsion between ephrin and Eph.We propose that Meltrin beta stabilizes the interaction between ephrin-A5 and EphA4 by regulating endocytosis of the ephrinA5-EphA complex negatively, which would contribute to the fine-tuning of the NMJ during development.

View Article: PubMed Central - PubMed

Affiliation: Department of Growth Regulation, Institute for Frontier Medical Sciences, Kyoto University, Shogo-in, Kyoto, Japan.

ABSTRACT

Background: Development of the neuromuscular junction (NMJ) is initiated by the formation of postsynaptic specializations in the central zones of muscles, followed by the arrival of motor nerve terminals opposite the postsynaptic regions. The post- and presynaptic components are then stabilized and modified to form mature synapses. Roles of ADAM (A Disintegrin And Metalloprotease) family proteins in the formation of the NMJ have not been reported previously.

Principal findings: We report here that Meltrin beta, ADAM19, participates in the formation of the NMJ. The zone of acetylcholine receptor alpha mRNA distribution was broader and excess sprouting of motor nerve terminals was more prominent in meltrin beta-deficient than in wild-type embryonic diaphragms. A microarray analysis revealed that the preferential distribution of ephrin-A5 mRNA in the synaptic region of muscles was aberrant in the meltrin beta-deficient muscles. Excess sprouting of motor nerve terminals was also found in ephrin-A5 knockout mice, which lead us to investigate a possible link between Meltrin beta and ephrin-A5-Eph signaling in the development of the NMJ. Meltrin beta and EphA4 interacted with each other in developing motor neurons, and both of these proteins localized in the NMJ. Coexpression of Meltrin beta and EphA4 strongly blocked vesicular internalization of ephrin-A5-EphA4 complexes without requiring the protease activity of Meltrin beta, suggesting a regulatory role of Meltrin beta in ephrin-A5-Eph signaling.

Conclusion: Meltrin beta plays a regulatory role in formation of the NMJ. The endocytosis of ephrin-Eph complexes is required for efficient contact-dependent repulsion between ephrin and Eph. We propose that Meltrin beta stabilizes the interaction between ephrin-A5 and EphA4 by regulating endocytosis of the ephrinA5-EphA complex negatively, which would contribute to the fine-tuning of the NMJ during development.

Show MeSH
Related in: MedlinePlus