Semaphorin3A Signaling Is Dispensable for Motor Axon Reinnervation of the Adult Neuromuscular Junction

Overview

Journal eNeuro

Specialty Neurology

Date 2018 May 19

PMID 29774231

Citations 7

Authors

Jennifer L Shadrach

Brian A Pierchala

Affiliations

Soon will be listed here.

Abstract

The neuromuscular junction (NMJ) is a specialized synapse that is formed by motor axon innervation of skeletal muscle fibers. The maintenance of motor-muscle connectivity is critical for the preservation of muscle tone and generation of movement. Injury can induce a robust regenerative response in motor axons, but severe trauma or chronic denervation resulting from neurodegenerative disease typically leads to inefficient repair and poor functional recovery. The axon guidance molecule Semaphorin3A (Sema3A) has been implicated as a negative regulator of motor innervation. Upon binding to a plexinA-neuropilin1 (Npn1) receptor complex, Sema3A initiates a downstream signaling cascade that results in axonal repulsion. Here, we established a reproducible nerve crush model to quantify motor nerve regeneration. We then used that model to investigate the role of Sema3A signaling at the adult NMJ. In contrast to previous findings, we found that and mRNA decrease in response to denervation, suggesting that Sema3A-Npn1 signaling may regulate NMJ reinnervation. To directly test that hypothesis, we used inducible knockout models to ubiquitously delete Sema3A or Npn1 from adult mice. Despite demonstrating that we could achieve highly efficient gene deletion, disruption of Sema3A-Npn1 signaling did not affect the normal maintenance of the NMJ or disrupt motor axon reinnervation after a denervating injury.

Citing Articles

Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration.

Schmitd L, Hafner H, Ward A, Asghari Adib E, Biscola N, Kohen R bioRxiv. 2024; .

PMID: 38496662 PMC: 10942360. DOI: 10.1101/2024.03.04.583374.

DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses.

Asghari Adib E, Shadrach J, Reilly-Jankowiak L, Dwivedi M, Rogers A, Shahzad S Cell Rep. 2024; 43(2):113801.

PMID: 38363678 PMC: 11088462. DOI: 10.1016/j.celrep.2024.113801.

Semaphorins: Missing Signals in Age-dependent Alteration of Neuromuscular Junctions and Skeletal Muscle Regeneration.

Fard D, Barbiera A, Dobrowolny G, Tamagnone L, Scicchitano B Aging Dis. 2023; 15(2):517-534.

PMID: 37728580 PMC: 10917540. DOI: 10.14336/AD.2023.0801.

Transcriptome profiling of a synergistic volumetric muscle loss repair strategy.

Roberts K, Kim J, Huynh T, Schluns J, Dunlap G, Hestekin J BMC Musculoskelet Disord. 2023; 24(1):321.

PMID: 37095469 PMC: 10124022. DOI: 10.1186/s12891-023-06401-1.

Increased Epidermal Nerve Growth Factor without Small-Fiber Neuropathy in Dermatomyositis.

Wong L, Lee C, Yen Y Int J Mol Sci. 2022; 23(16).

PMID: 36012289 PMC: 9408946. DOI: 10.3390/ijms23169030.

References

Soker S, Takashima S, Miao H, Neufeld G, Klagsbrun M . Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998; 92(6):735-45. DOI: 10.1016/s0092-8674(00)81402-6. View

Dalkin W, Taetzsch T, Valdez G . The Fibular Nerve Injury Method: A Reliable Assay to Identify and Test Factors That Repair Neuromuscular Junctions. J Vis Exp. 2016; (114). PMC: 5091792. DOI: 10.3791/54186. View

Omoto M, Yoshida S, Miyashita H, Kawakita T, Yoshida K, Kishino A . The semaphorin 3A inhibitor SM-345431 accelerates peripheral nerve regeneration and sensitivity in a murine corneal transplantation model. PLoS One. 2012; 7(11):e47716. PMC: 3494696. DOI: 10.1371/journal.pone.0047716. View

Masahira N, Takebayashi H, Ono K, Watanabe K, Ding L, Furusho M . Olig2-positive progenitors in the embryonic spinal cord give rise not only to motoneurons and oligodendrocytes, but also to a subset of astrocytes and ependymal cells. Dev Biol. 2006; 293(2):358-69. DOI: 10.1016/j.ydbio.2006.02.029. View

Behar O, Golden J, Mashimo H, Schoen F, Fishman M . Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature. 1996; 383(6600):525-8. DOI: 10.1038/383525a0. View

Xu Q, Midha R, Martinez J, Guo G, Zochodne D . Facilitated sprouting in a peripheral nerve injury. Neuroscience. 2008; 152(4):877-87. DOI: 10.1016/j.neuroscience.2008.01.060. View

Valenzuela D, Stitt T, DiStefano P, Rojas E, Mattsson K, Compton D . Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron. 1995; 15(3):573-84. DOI: 10.1016/0896-6273(95)90146-9. View

Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P . Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci. 2000; 20(7):2534-42. PMC: 6772256. View

Agbulut O, Noirez P, Beaumont F, Butler-Browne G . Myosin heavy chain isoforms in postnatal muscle development of mice. Biol Cell. 2003; 95(6):399-406. DOI: 10.1016/s0248-4900(03)00087-x. View

10.

Schmidt E, Pasterkamp R, van den Berg L . Axon guidance proteins: novel therapeutic targets for ALS?. Prog Neurobiol. 2009; 88(4):286-301. DOI: 10.1016/j.pneurobio.2009.05.004. View

11.

Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano M, Appelmans S, Oh H . Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci. 2004; 8(1):85-92. DOI: 10.1038/nn1360. View

12.

Morita A, Yamashita N, Sasaki Y, Uchida Y, Nakajima O, Nakamura F . Regulation of dendritic branching and spine maturation by semaphorin3A-Fyn signaling. J Neurosci. 2006; 26(11):2971-80. PMC: 6673984. DOI: 10.1523/JNEUROSCI.5453-05.2006. View

13.

Shelly M, Cancedda L, Lim B, Popescu A, Cheng P, Gao H . Semaphorin3A regulates neuronal polarization by suppressing axon formation and promoting dendrite growth. Neuron. 2011; 71(3):433-46. PMC: 3164872. DOI: 10.1016/j.neuron.2011.06.041. View

14.

Kitsukawa T, Shimizu M, Sanbo M, Hirata T, Taniguchi M, Bekku Y . Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron. 1997; 19(5):995-1005. DOI: 10.1016/s0896-6273(00)80392-x. View

15.

Haupt C, Kloos K, Faus-Kessler T, Huber A . Semaphorin 3A-Neuropilin-1 signaling regulates peripheral axon fasciculation and pathfinding but not developmental cell death patterns. Eur J Neurosci. 2010; 31(7):1164-72. DOI: 10.1111/j.1460-9568.2010.07154.x. View

16.

Yaron A, Zheng B . Navigating their way to the clinic: emerging roles for axon guidance molecules in neurological disorders and injury. Dev Neurobiol. 2007; 67(9):1216-31. DOI: 10.1002/dneu.20512. View

17.

Gumerson J, Davis C, Kabaeva Z, Hayes J, Brooks S, Michele D . Muscle-specific expression of LARGE restores neuromuscular transmission deficits in dystrophic LARGE(myd) mice. Hum Mol Genet. 2012; 22(4):757-68. PMC: 3554202. DOI: 10.1093/hmg/dds483. View

18.

Kaneko S, Iwanami A, Nakamura M, Kishino A, Kikuchi K, Shibata S . A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nat Med. 2006; 12(12):1380-9. DOI: 10.1038/nm1505. View

19.

Helmbrecht M, Soellner H, Truckenbrodt A, Sundermeier J, Cohrs C, Hans W . Loss of Npn1 from motor neurons causes postnatal deficits independent from Sema3A signaling. Dev Biol. 2014; 399(1):2-14. DOI: 10.1016/j.ydbio.2014.11.024. View

20.

Luo Y, Raible D, Raper J . Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993; 75(2):217-27. DOI: 10.1016/0092-8674(93)80064-l. View