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.
Highlights
1.1 Basic anatomy of sensory ganglia and spinal nervesLarge peripheral nerves usually carry a sensory and a motor component
Whereas the cell bodies of motor axons are located in the spinal cord, the sensory neurons are found in the dorsal root ganglia (DRG)
Neurons can be identified with specific markers such as neurofilament 200 for myelinating large sized neurons, whereas unmyelinated axons are mainly derived from Isolectin Beta 4 (IB4) binding or calcitonin gene related peptide (CGRP) positive neurons of small to medium size
Summary
1.1 Basic anatomy of sensory ganglia and spinal nervesLarge peripheral nerves usually carry a sensory and a motor component. Whereas the cell bodies of motor axons are located in the spinal cord, the sensory neurons are found in the dorsal root ganglia (DRG). DRG are composed of small and large sized neurons surrounded by satellite cells. Axons originate and branch in a T-like fashion into the central (dorsal) nerve root and into the spinal nerve, respectively. The central root is connected to the spinal cord, whereas the peripheral branch innervates muscles, viscera and skin. Based on morphological and ultrastructural features, DRG neurons can be categorized into three neuronal subpopulations, the thermonociceptors, mechanoreceptors and proprioceptors, which in general correspond to small, medium and large neurons, respectively.
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