Synapses Form in Skeletal Muscles Lacking Neuregulin Receptors

P. Escher,^1* E. Lacazette,^1* M. Courtet,¹ A. Blindenbacher,¹ L. Landmann,² G. Bezakova,³ K. C. Lloyd,⁴ U. Mueller,⁵ H. R. Brenner¹

Abstract: The formation of the neuromuscular junction (NMJ) is directed by reciprocal interactions between motor neurons and muscle fibers. Neuregulin (NRG) and Agrin from motor nerve terminals are both implicated. Here, we demonstrate that NMJs can form in the absence of the NRG receptors ErbB2 and ErbB4 in mouse muscle. Postsynaptic differentiation is, however, induced by Agrin. We therefore conclude that NRG signaling to muscle is not required for NMJ formation. The effects of NRG signaling to muscle may be mediated indirectly through Schwann cells.

¹ Institute of Physiology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
² Institute of Anatomy, Department of Clinical-Biological Sciences, Biozentrum, University of Basel, 4056 Basel, Switzerland.
³ Division of Pharmacology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
⁴ Center for Comparative Medicine, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
⁵ Department of Cell Biology and Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, CA 92037, USA.

To whom correspondence should be addressed. E-mail: Hans-Rudolf.Brenner{at}unibas.ch

Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane.

N. Schmidt, S. Basu, S. Sladecek, S. Gatti, J. van Haren, S. Treves, J. Pielage, N. Galjart, and H. R. Brenner (2012)
J. Cell Biol. 198, 421-437
 |  Abstract »  |  Full Text »  |  PDF »

Neuregulin-1 potentiates agrin-induced acetylcholine receptor clustering through muscle-specific kinase phosphorylation.

S. T. Ngo, R. N. Cole, N. Sunn, W. D. Phillips, and P. G. Noakes (2012)
J. Cell Sci. 125, 1531-1543
 |  Abstract »  |  Full Text »  |  PDF »

Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of {alpha}-dystrobrevin.

N. Schmidt, M. Akaaboune, N. Gajendran, I. Martinez-Pena y Valenzuela, S. Wakefield, R. Thurnheer, and H. R. Brenner (2011)
J. Cell Biol. 195, 1171-1184
 |  Abstract »  |  Full Text »  |  PDF »

Axonally Derived Neuregulin-1 Is Required for Remyelination and Regeneration after Nerve Injury in Adulthood.

F. R. Fricker, N. Lago, S. Balarajah, C. Tsantoulas, S. Tanna, N. Zhu, S. K. Fageiry, M. Jenkins, A. N. Garratt, C. Birchmeier, et al. (2011)
J. Neurosci. 31, 3225-3233
 |  Abstract »  |  Full Text »  |  PDF »

Identification of Erbin Interlinking MuSK and ErbB2 and Its Impact on Acetylcholine Receptor Aggregation at the Neuromuscular Junction.

L. Simeone, M. Straubinger, M. A. Khan, N. Nalleweg, T. Cheusova, and S. Hashemolhosseini (2010)
J. Neurosci. 30, 6620-6634
 |  Abstract »  |  Full Text »  |  PDF »

To build a synapse: signaling pathways in neuromuscular junction assembly.

H. Wu, W. C. Xiong, and L. Mei (2010)
Development 137, 1017-1033
 |  Abstract »  |  Full Text »  |  PDF »

Emerging role of neuregulin as a modulator of muscle metabolism.

A. Guma, V. Martinez-Redondo, I. Lopez-Soldado, C. Canto, and A. Zorzano (2010)
Am J Physiol Endocrinol Metab 298, E742-E750
 |  Abstract »  |  Full Text »  |  PDF »

Neuregulin Signaling Is Dispensable for NMDA- and GABAA-Receptor Expression in the Cerebellum In Vivo.

N. Gajendran, J. P. Kapfhammer, E. Lain, M. Canepari, K. Vogt, W. Wisden, and H. R. Brenner (2009)
J. Neurosci. 29, 2404-2413
 |  Abstract »  |  Full Text »  |  PDF »

Dual Constraints on Synapse Formation and Regression in Schizophrenia: Neuregulin, Neuroligin, Dysbindin, DISC1, MuSK and Agrin.

M. R. Bennett Ao (2008)
Australian and New Zealand Journal of Psychiatry 42, 662-677
 |  Abstract »  |  Full Text »  |  PDF »

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death.

I. Ksiazek, C. Burkhardt, S. Lin, R. Seddik, M. Maj, G. Bezakova, M. Jucker, S. Arber, P. Caroni, J. R. Sanes, et al. (2007)
J. Neurosci. 27, 7183-7195
 |  Abstract »  |  Full Text »  |  PDF »

Targeting of the ETS Factor Gabp{alpha} Disrupts Neuromuscular Junction Synaptic Function.

D. A. O'Leary, P. G. Noakes, N. A. Lavidis, I. Kola, P. J. Hertzog, and S. Ristevski (2007)
Mol. Cell. Biol. 27, 3470-3480
 |  Abstract »  |  Full Text »  |  PDF »

PGC-1{alpha} regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy.

C. Handschin, Y. M. Kobayashi, S. Chin, P. Seale, K. P. Campbell, and B. M. Spiegelman (2007)
Genes & Dev. 21, 770-783
 |  Abstract »  |  Full Text »  |  PDF »

Differential requirement for MuSK and dystroglycan in generating patterns of neuromuscular innervation.

J. L. Lefebvre, L. Jing, S. Becaficco, C. Franzini-Armstrong, and M. Granato (2007)
PNAS 104, 2483-2488
 |  Abstract »  |  Full Text »  |  PDF »

Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction..

T. Cheusova, M. A. Khan, S. W. Schubert, A.-C. Gavin, T. Buchou, G. Jacob, H. Sticht, J. Allende, B. Boldyreff, H. R. Brenner, et al. (2006)
Genes & Dev. 20, 1800-1816
 |  Abstract »  |  Full Text »  |  PDF »

Neuromuscular Synapse Formation in Mice Lacking Motor Neuron- and Skeletal Muscle-Derived Neuregulin-1.

A. Jaworski and S. J. Burden (2006)
J. Neurosci. 26, 655-661
 |  Abstract »  |  Full Text »  |  PDF »

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice.

A. K. Y. Fu, F. C. F. Ip, W.-Y. Fu, J. Cheung, J. H. Wang, W.-H. Yung, and N. Y. Ip (2005)
PNAS 102, 15224-15230
 |  Abstract »  |  Full Text »  |  PDF »

Highlights from the Literature.

(2005)
Physiology 20, 287-291
 |  Full Text »  |  PDF »