Differential effects of ret and TRKB on axonal branching and survival of parasympathetic neurons

Abstract

Interactions between neurons and their targets of innervation influence many aspects of neural development. To examine how synaptic activity interacts with neurotrophic signaling, we determined the effects of blocking neuromuscular transmission on survival and axonal outgrowth of ciliary neurons from the embryonic chicken ciliary ganglion. Ciliary neurons undergo a period of cell loss due to programmed cell death between embryonic Days (E) 8 and 14 and they innervate the striated muscle of the iris. The nicotinic antagonist d-tubocurarine (dTC) induces an increase in branching measured by counting neurofilament-positive voxels (NF-VU) in the iris between E14–17 while reducing ciliary neuron survival. Blocking ganglionic transmission with dihyro-β-erythroidin and α-methyllycacontine does not mimic dTC. At E8, many trophic factors stimulate neurite outgrowth and branching of neurons placed in cell culture; however, at E13, only GDNF stimulates branching selectively in cultured ciliary neurons. The GDNF-induced branching at E13 could be inhibited by BDNF. Blocking ret signaling in vivo with a dominant negative (dn)ret decreases survival of ciliary and choroid neurons at E14 and prevents dTC induced increases in NF-VU in the iris at E17. Blocking TRKB signaling with dn TRKB increases NF-VU in the iris at E17 and decreases neuronal survival at E17, but not at E14. Thus, RET promotes survival during programmed cell death in the ciliary ganglion and contributes to promoting branching when synaptic transmission is blocked while TRKB inhibits branching and promotes maintenance of neuronal survival. These studies highlight the multifunctional nature of trophic molecule function during neuronal development.

Knockdown of CXCL14 disrupts neurovascular patterning during ocular development

“…Similar to CXCL14 knockdown in the cornea, we observed extensive iridial innervation, which originate from the trigeminal and ciliary ganglia (Kuwayama and Stone, 1987; Neuhuber and Schödl, 2011; Simpson et al, 2013). We also noticed numerous Tuj1-positive cells that remained unincorporated into the iridial nerve plexus in CXCL14 knockdown eyes.…”

“…Subsequently, nerves from the trigeminal and ciliary ganglia project into the anterior eye and innervate the cornea and iris (Bee et al, 1982; Lwigale and Bronner-Fraser, 2007; Pilar et al, 1980; Simpson et al 2013), and the inner layer of the optic cup differentiates into photo sensory cells and neurons of the neural retina (Adler and Hatlee, 1989; Cepko et al, 1996). Also, during ocular development, endothelial cells located in the periocular region form a dense limbal vascular network (Kwiatkwoski et al, 2013; McKenna et al, 2014).…”

“…Sensory nerves are attracted to the anterior eye by neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF) that are secreted by the cornea (Lambiase et al, 1997; You et al, 2000) and iris (Simpson et al 2013). However, nerve projection into the cornea is regulated by Semaphorins secreted mainly by the lens (Lwigale and Bronner-Fraser, 2007; McKenna et al, 2012) and Robo-slit signaling (Kubilus and Linsenmayer, 2010; Schwend et al, 2012).…”

Estrogen and female reproductive tract innervation: Cellular and molecular mechanisms of autonomic neuroplasticity

“…Uterine-projecting preganglionic and postganglionic parasympathetic neurons located in rat paracervical ganglia express immunoreactivity for estrogen receptors α and β (Williams and Papka 1996; Papka et al 1997, 2001; Williams et al 1997; Papka and Mowa, 2003). In addition, immature and adult cholinergic neurons are receptive to several trophic and axon guidance factors (i.e., Laurikainen et al, 2000; Nangle and Keast, 2001; Hasan, 2013; Simpson et al, 2013). It is therefore possible, that estrogen regulates plasticity in immature cholinergic nerves via direct effects on neurons as well as through alterations in neuron-target interactions.…”

RARβ regulates neuronal cell death and differentiation in the avian ciliary ganglion

“…The chicken ciliary ganglion (CG) is a classical model to study PCD and neuronal differentiation during development, with a well characterized 50% decline in neuron number between embryonic day 8 and 14 (E8-E14) (Landmesser and Pilar, 1974;Hamburger, 1975). There is a vast body of literature concerning PCD in the CG, discussing it as an extrinsically regulated process, guided either by the establishment of a functional balance between preganglionic and postganglionic activity (Furber et al, 1987;Meriney et al, 1987;Collins et al, 1991) or the availability of target-derived neurotrophic factors, such as CNTF, BDNF, and GDNF (Barbin et al, 1984;Dreyer et al, 1989;Simpson et al, 2013). Moreover, TGFbs were shown to be modulators of cell death in the CG (Krieglstein et al, 2000).…”