Axonal outgrowth from adult mouse nodose gangliain vitro is stimulated by neurotrophin-4 in a Trk receptor and mitogen-activated protein kinase-dependent way

Abstract

The actions of neurotrophic factors on sensory neurons of the adult nodose ganglion were studied in vitro. The ganglia were explanted in an extracellular matrix–based gel that permitted observation of the growing axons. Neurotrophin‐4 (NT‐4) was a very efficient stimulator of outgrowth of axons from the nodose ganglion and had almost doubled the outgrowth length when this was analyzed after 2 days in culture. Brain‐derived neurotrophic factor also stimulated outgrowth, but to a lesser degree, whereas NT‐3 gave only weak stimulatory tendencies. Nerve growth factor and glial cell line–derived neurotrophic factor both lacked stimulatory effects. NT‐4 is known to act via TrkB receptors, and the presence of these on growing nodose neurons was demonstrated immunohistochemically. In line with a Trk‐mediated growth effect, the NT‐4 stimulation was abolished by K252a, a selective inhibitor of neurotrophin receptor–associated tyrosine kinase activity. K252a had no effect on the unstimulated preparation. NT‐4 treatment led to activation of the mitogen‐activated protein kinase and inhibition of the latter pathway by PD98059 significantly reduced the NT‐4 stimulated outgrowth, whereas the drug had no effect on the unstimulated growth. In conclusion, the data suggest that NT‐4 can serve as a powerful growth factor for neurons of adult nodose ganglia and that the growth stimulation involves TrkB‐ and mitogen‐activated protein kinase. © 2000 John Wiley & Sons, Inc. J Neurobiol 45: 142–151, 2000

Development of the vagal innervation of the gut: steering the wandering nerve

“…The available evidence suggests this loss of intestinal IGLEs could have resulted from loss of NT‐4 axon guidance or survival functions. Consistent with this interpretation, NT‐4 supports survival of cultured developing nodose ganglion neurons 80 and induces axon outgrowth from the adult nodose ganglion in vitro 81 . NT‐4, moreover, is expressed in visceral tissues 82 traversed by vagal sensory axons growing toward the GI tract.…”

“…Consistent with this interpretation, NT-4 supports survival of cultured developing nodose ganglion neurons 80 and induces axon outgrowth from the adult nodose ganglion in vitro. 81 NT-4, moreover, is expressed in visceral tissues 82 traversed by vagal sensory axons growing toward the GI tract. NT-4 deficiency has effects in other neural systems, including loss of a large population of P2X3-expressing vagal sensory nerves that innervate the neuroepithelial bodies in the lung and may be mechanoreceptors, 83 loss of adult down hair cutaneous mechanoreceptors, 84 loss of sympathetic neurons that innervate the adrenal medulla, 85 and a partial loss of gustatory innervation.…”

Impaired Axonal Regeneration by Isolectin B4-Binding Dorsal Root Ganglion NeuronsIn Vitro

“…NGF, NT-3, and GDNF also promote axonal regeneration of adult neurons (Mohiuddin et al, 1995;Edström et al, 1996;Naveilhan et al, 1997;Leclere et al, 1998;Gavazzi et al, 1999;Ramer et al, 2000;Fine et al, 2002). BDNF does not stimulate growth of DRG axons in adult rodents (Malgrange et al, 1994;Edström et al, 1996;Kimpinski et al, 1997;Gavazzi et al, 1999), but BDNF and NT-4 both stimulate axonal growth from nodose ganglia (Wiklund and Ekström, 2000). After peripheral nerve (PN) lesions, synthesis of NGF, BDNF, NT-4, and GDNF increases (Meyer et al, 1992;Funakoshi et al, 1993;Trupp et al, 1995;Naveilhan et al, 1997;Bar et al, 1998;Hoke et al, 2000Hoke et al, , 2002Dethleffsen et al, 2002).…”

Vagal activities are involved in antigen‐specific immune inflammation in the intestine

“…Mouse nodose ganglion neurons were isolated and cultured following published procedures. 11 Briefly, after decapitation, nodose ganglia were excised and incubated for 30-50 min in phosphatebuffered saline (PBS) containing 0.3% trypsin and 0.1% collagenase at 32°C. Throughout the entire procedure, the medium was continuously saturated with a 95% O2/5% CO2 gas mixture (pH 7.4).…”