NGF-dependent axon growth and regeneration are altered in sympathetic neurons of dystrophic mdx mice.
Duchenne muscular dystrophy (DMD) is a lethal disease, determined by lack of dystrophin (Dp427), a muscular cytoskeletal protein also expressed by selected neuronal populations. Consequently, besides muscular wasting, both human patients and DMD animal models suffer several neural disorders. In previous studies on the superior cervical ganglion (SCG) of wild type and dystrophic mdx mice (Lombardi et al. 2008), we hypothesized that Dp427 could play some role in NGF-dependent axonal growth, both during development and adulthood. To address this issue, we first analyzed axon regeneration potentials of SCG neurons of both genotypes after axotomy in vivo. While noradrenergic innervation of mdx mouse submandibular gland, main source of nerve growth factor (NGF), recovered similarly to wild type, iris innervation (muscular target) never did. We, therefore, evaluated whether dystrophic SCG neurons were poorly responsive to NGF, especially at low concentration. Following in vitro axotomy in the presence of either 10 or 50ng/ml NGF, the number of regenerated axons in mdx mouse neuron cultures was indeed reduced, compared to wild type, at the lower concentration. Neurite growth parameters (i.e. number, length), growth cone dynamics and NGF/TrkA receptor signaling in differentiating neurons (not injured) were also significantly reduced when cultured with 10ng/ml NGF, but also with higher NGF concentrations. In conclusion, we propose a role for Dp427 in NGF-dependent cytoskeletal dynamics associated to growth cone advancement, possibly through indirect stabilization of TrkA receptors. Considering NGF activity in nervous system development/remodeling, this aspect could concur in some of the described DMD-associated neural dysfunctions.
Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, 00185 Roma, Italy.
Loredana
L
Lombardi
Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, 00185 Roma, Italy.
Irene
I
Persiconi
Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, 00185 Roma, Italy.
Alessandra
A
Gallo
Cell Biology, Faculty of Science, Utrecht University, 3584CH Utrecht, The Netherlands.
Casper C
CC
Hoogenraad
Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, 00185 Roma, Italy; Center for Research in Neurobiology "Daniel Bovet", Sapienza Università di Roma, 00185 Roma, Italy. Electronic address: egle.destefano@uniroma1.it.
Maria Egle
ME
De Stefano
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects* / Q000648:ultrastructure; D019771:Axotomy; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D049030:Dystroglycans / Q000378:metabolism; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D007498:Iris / Q000294:innervation; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D020813:Receptor, trkB / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000166:cytology*; D014404:Tubulin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D016189:Dystrophin; D009419:Nerve Tissue Proteins; D014404:Tubulin; D049030:Dystroglycans; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D020813:Receptor, trkB; D053148:Caspase 3
Axon growth; Axon regeneration; Duchenne muscular dystrophy; Dystrophin-dystroglycan complex; NGF signaling; TrkA receptor; mdx mice