title: Enhanced axon outgrowth and improved long-distance axon regeneration in sprouty2 deficient mice.
abstract: Sprouty (Spry) proteins are negative feedback inhibitors of receptor tyrosine kinase signaling. Downregulation of Spry2 has been demonstrated to promote elongative axon growth of cultured peripheral and central neurons. Here, we analyzed Spry2 global knockout mice with respect to axon outgrowth in vitro and peripheral axon regeneration in vivo. Neurons dissociated from adult Spry2 deficient sensory ganglia revealed stronger extracellular signal-regulated kinase activation and enhanced axon outgrowth. Prominent axon elongation was observed in heterozygous Spry2(+/-) neuron cultures, whereas homozygous Spry2(-/-) neurons predominantly exhibited a branching phenotype. Following sciatic nerve crush, Spry2(+/-) mice recovered faster in motor but not sensory testing paradigms (Spry2(-/-) mice did not tolerate anesthesia required for nerve surgery). We attribute the improvement in the rotarod test to higher numbers of myelinated fibers in the regenerating sciatic nerve, higher densities of motor endplates in hind limb muscles and increased levels of GAP-43 mRNA, a downstream target of extracellular regulated kinase signaling. Conversely, homozygous Spry2(-/-) mice revealed enhanced mechanosensory function (von Frey's test) that was accompanied by an increased innervation of the epidermis, elevated numbers of nonmyelinated axons and more IB4-positive neurons in dorsal root ganglia. The present results corroborate the functional significance of receptor tyrosine kinase signaling inhibitors for axon outgrowth during development and nerve regeneration and propose Spry2 as a novel potential target for pharmacological inhibition to accelerate long-distance axon regeneration in injured peripheral nerves.
authors.affiliation: Division of Neuroanatomy, Department of Anatomy and Histology, Medical University Innsbruck, 6020, Innsbruck, Austria.
authors.forename: Letizia
authors.initials: L
authors.lastname: Marvaldi
authors.forename: Sitthisak
authors.initials: S
authors.lastname: Thongrong
authors.forename: Anna
authors.initials: A
authors.lastname: Kozłowska
authors.forename: Regina
authors.initials: R
authors.lastname: Irschick
authors.forename: Christian O
authors.initials: CO
authors.lastname: Pritz
authors.forename: Bastian
authors.initials: B
authors.lastname: Bäumer
authors.forename: Giulia
authors.initials: G
authors.lastname: Ronchi
authors.forename: Stefano
authors.initials: S
authors.lastname: Geuna
authors.forename: Barbara
authors.initials: B
authors.lastname: Hausott
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D019922:GAP-43 Protein / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009416:Nerve Regeneration / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D020127:Recovery of Function / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D019922:GAP-43 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse
keywords: axotomy; fibroblast growth factor; ganglion; innervation; motor; nerve growth factor; sensory