A Distinct Subgroup of Small DRG Cells Express GDNF Receptor Components and GDNF Is Protective for These Neurons after Nerve Injury

Abstract

Several lines of evidence suggest that neurotrophin administration may be of some therapeutic benefit in the treatment of peripheral neuropathy. However, a third of sensory neurons do not express receptors for the neurotrophins. These neurons are of small diameter and can be identified by the binding of the lectin IB4 and the expression of the enzyme thiamine monophosphatase (TMP). Here we show that these neurons express the receptor components for glial-derived neurotrophic factor (GDNF) signaling (RET, GFRalpha-1, and GFRalpha-2). In lumbar dorsal root ganglia, virtually all IB4-labeled cells express RET mRNA, and the majority of these cells (79%) also express GFRalpha-1, GFRalpha-2, or GFRalpha-1 plus GFRalpha-2. GDNF, but not nerve growth factor (NGF), can prevent several axotomy-induced changes in these neurons, including the downregulation of IB4 binding, TMP activity, and somatostatin expression. GDNF also prevents the slowing of conduction velocity that normally occurs after axotomy in a population of small diameter DRG cells and the A-fiber sprouting into lamina II of the dorsal horn. GDNF therefore may be useful in the treatment of peripheral neuropathies and may protect peripheral neurons that are refractory to neurotrophin treatment.

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…160 GDNF promoted the regeneration of large-and small-caliber axons, in line with the expression patterns of the requisite receptors. 161,162 Encouragingly, regrowth was accompanied by synaptic reconnection, again in a selective fashion, such that NGF and GDNF treatments resulted in reactivation of dorsal horn neurons by slowly conducting (smaller diameter) sensory axons, and NT-3 and GDNF treatments facilitated the recovery of postsynaptic potentials that are evoked by rapidly conducting (larger diameter) sensory fibers. NGF-and GDNF-treated animals regained the ability to sense pain, indicating that appropriate spinal circuits were being activated by sensory input.…”

Progress in Spinal Cord Research - A refined strategy for the International Spinal Research Trust

“…It has been known for some time that neurotrophins regulate the terminal arborisation of some types of axons: in the PNS, NGF regulates the complexity of primary a erent terminations in the skin, as well as sympathetic axonal and dendritic morphology. 124,125 In the CNS, NGF and GDNF can prevent aberrant terminal arborisation associated with peripheral nerve injury, 126,127 and BDNF promotes the terminal branching of retinal ganglion axons in the optic tectum. 128 A second form of axon branching occurs long after a parent axon has navigated its course, and a daughter axon sprouts as a collateral from somewhere along its length.…”

“…152 ± 154 Treatment with the trophic factors NGF and GDNF have been shown to reverse the aberrant dorsal horn sprouting observed after a peripheral axotomy. 126,127 Thus, in the case of SCI, treatment strategies may need to be designed which strike a balance between harnessing bene®cial sprouting responses and controlling compensatory but unproductive sprouting of axon collaterals.…”

“…184 Intrinsic markers, however, have disadvantages as in some cases there are other populations of spinal cord neurons which also express them (interneurons in the dorsal horn, for example, also express PKCg 181 ), or their expression may be modulated as a result of injury, or by treatment with pharmacological agents such as neurotrophic factors (e.g. 127,185 ). This means that comparisons of axonal distributions between the intact state, the injury state, and injury-plus-treatment state can be easily muddied.…”

The role of glial cells in influencing neurite extension by dorsal root ganglion cells

“…Small diameter neurons have unmyelinated or lightly myelinated axons and are responsible for nociception (Priestley et al, 2002). Small diameter neurons can be further separated into two different subpopulations: (1) peptidergic neurons, which respond to NGF and express neuropeptides such as substance P and calcitonin-gene-related peptide (CGRP) (Snider and McMahon, 1998) and (2) non-peptidergic neurons, which respond to glial cell line-derived neurotrophic factor (GDNF) (Molliver et al, 1997;Bennett et al, 1998;Snider and McMahon, 1998). In addition, neurons are identified by binding of lectins such as Griffonia simplicifolia isolectin B 4 (IB4); IB4-positive (IB4 þve) neurons are GDNF-responsive (small diameter) and the IB4-negative (IB4 2ve) neurons are NGF-responsive (large and small diameter) (Julius and Basbaum, 2001).…”