Distribution of GDNF family receptor α3 and RET in rat and human non-neural tissues

Abstract

The neurotrophic growth factor artemin binds selectively to GDNF family receptor alpha3 (GFRalpha3), forming a molecular complex with the co-receptor RET which mediates downstream signaling. This signaling pathway has been demonstrated to play an important role in the survival and maintenance of nociceptive sensory neurons and in the development of sympathetic neurons. However, the presence and potential role of this artemin-responsive pathway in non-neural tissues has not been fully explored to-date. To study the distribution of GFRalpha3 and RET in adult rat and human non-neural tissues, we carried out a comprehensive immunohistochemical study. We stained major organs from the digestive, urinary, reproductive, immune, respiratory and endocrine systems, and from other systems (cardiovascular, skeletal muscle), as well as regions of the nervous system for comparison. In both rat and human, the majority of non-neural cells did not exhibit detectable GFRalpha3-like immunoreactivity. In the rat, GFRalpha3- and RET-like staining were found in the same non-neural cell type only in kidney. In the human digestive and reproductive systems, a subset of epithelial cells exhibited GFRalpha3- and RET-like staining, suggesting co-localization. In other tissues, sub-populations of cells expressed either GFRalpha3- or RET-like immunoreactivity. The functional consequences of GFRalpha3 expression in non-neural cells remain to be determined.

Neurturin Influences Inflammatory Responses and Airway Remodeling in Different Mouse Asthma Models

“…Because we observed the expression of GFRa-2 and RET mRNA in lung tissues, in immune and epithelial cells, this suggests a direct action of NTN on DCs and T cells. Our results are in accordance with previous reports, which described that mice and human lung, LN, and immune cell subsets like CD4 + T cells and monocytes are able to produce NTN and express its receptors GFRa-2 and RET (29,(38)(39)(40)(41). Furthermore, after a stimulation with OVA and NTN in a culture of DCs or the LA-4 cell line, the IL-6 levels were lower in comparison with the condition with OVA alone.…”

Artemin-Stimulated Progression of Human Non–Small Cell Lung Carcinoma Is Mediated by BCL2

“…Additionally, expression of GFRA3 is detectable in the normal lung and bronchus of human and mouse (29,30). RET expression has also been shown in normal human lung (30). These facts together suggest that an autocrine ARTN signaling pathway is functional in human lung and the excessive activity of this pathway may therefore promote disease progression in lung carcinoma.…”

“…Additionally, expression of GFRA3 is detectable in the normal lung and bronchus of human and mouse (29,30). RET expression has also been shown in normal human lung (30).…”

Novel Therapeutic Modalities to Address Nondrugable Protein Interaction Targets

“…Like GDNF, artemin supports the survival of cultured sensory neurons (Baloh et al, 1998a, b). However, the distribution pattern of artemin's receptor, GFRa3, is relatively restricted, being expressed predominantly in adult rodent and human nociceptive sensory neurons (Orozco et al, 2001;Yang et al, 2006), suggesting that artemin would specifically modulate the pain sensory system in the adult. This was established in the rat spinal nerve ligation model where behavioral, neurochemical, and histochemical changes associated with neuropathic pain were reversed with systemic administration of artemin (Gardell et al, 2003).…”

“…This was established in the rat spinal nerve ligation model where behavioral, neurochemical, and histochemical changes associated with neuropathic pain were reversed with systemic administration of artemin (Gardell et al, 2003). More recently, expression of GFRa3 immunoreactivity has also been reported in other tissues, including a subset of epithelial cells in the digestive and reproductive systems; the functional consequences of this expression remain to be determined (Yang et al, 2006). In contrast to small molecule drugs targeting individual ion channels or neurotransmitter receptors, these protein-based therapeutic strategies represent novel and promising approaches for the treatment of chronic pain that have the potential to impact multiple facets of pathology.…”