Type III neuregulin 1 regulates pathfinding of sensory axons in the developing spinal cord and periphery

Abstract

SUMMARYSensory axons must develop appropriate connections with both central and peripheral targets. Whereas the peripheral cues have provided a classic model for neuron survival and guidance, less is known about the central cues or the coordination of central and peripheral connectivity. Here we find that type III Nrg1, in addition to its known effect on neuron survival, regulates axon pathfinding. In type III Nrg1 -/-mice, death of TrkA + nociceptive/thermoreceptive neurons was increased, and could be rescued by Bax elimination. In the Bax and type III Nrg1 double mutants, axon pathfinding abnormalities were seen for TrkA + neurons both in cutaneous peripheral targets and in spinal cord central targets. Axon guidance phenotypes in the spinal cord included penetration of axons into ventral regions from which they would normally be repelled by Sema3A. Accordingly, sensory neurons from type III Nrg1 -/-mice were unresponsive to the repellent effects of Sema3A in vitro, which might account, at least in part, for the central projection phenotype, and demonstrates an effect of type III Nrg1 on guidance cue responsiveness in neurons. Moreover, stimulation of type III Nrg1 back-signaling in cultured sensory neurons was found to regulate axonal levels of the Sema3A receptor neuropilin 1. These results reveal a molecular mechanism whereby type III Nrg1 signaling can regulate the responsiveness of neurons to a guidance cue, and show that type III Nrg1 is required for normal sensory neuron survival and axon pathfinding in both central and peripheral targets.

Neurotrophin selectivity in organizing topographic regeneration of nociceptive afferents

“…Although multiple mechanisms for NGF induced CGRP-IR axon sprouting or mistargeted regeneration have been hypothesized (Tang et al, 2004; Hannila and Kawaja, 2005; Hancock et al, 2011), our present data indicate this phenomenon to be related to the well documented role of NGF in axon collateral branch formation (Diamond et al, 1985; Doubleday and Robinson, 1992; Harper et al, 1999). Theoretically, if NGF induced axonal trapping within the region of NGF expression, then synapses associated with trapped axons should be randomly distributed in this region.…”

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…This isoform has been implicated in axonal pathfinding of TrkA+ sensory neurons in response to Sema3A, a guidance cue in the developing spinal cord and in the periphery (Hancock et al, 2011) and in regulating functional TRPV1 along sensory neuron axons for heat sensing (Canetta et al, 2011). Its most important function is the control of Schwann cell development and peripheral myelination.…”

MicroRNA-132 Is Enriched in Developing Axons, Locally Regulates Rasa1 mRNA, and Promotes Axon Extension

“…Whole-mount ␤-galactosidase staining was performed as described previously (Sanes et al, 1986). Immunolabeling was performed as described previously (Hancock et al, 2011) using the following antibodies: mouse anti-Islet1/2 (1:1000, Developmental Studies Hybridoma Bank 39.4D5); rabbit anti-peripherin (1:500, Millipore Bioscience Research Reagents); rabbit anti-TrkA (1:1000, L. Reichardt, University of California, San Francisco); rabbit anti-Argonaute 2 (1:100, Cell Signaling Technology); mouse anti-Dicer (1:100, Abcam); rabbit anti-GFP (1:2000, Invitrogen); rabbit anti-NF-M (1:1000, Millipore Bioscience Research Reagents); mouse anti-Ras GAP (1:400, Santa Cruz Biotechnology); or rabbit anti-Tuj1 (1:500, Abcam), followed by Alexa fluorophoreconjugated secondary antibodies (1:500, Invitrogen), and mounted with Fluoromount-G (SouthernBiotech). As a negative control, cells were immunolabeled with secondary antibody alone to verify an absence of nonspecific background signal caused by secondary antibodies.…”