Abstract
The neurotrophic growth factor artemin binds selectively to GDNF family receptor α3 (GFRα3), 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 GFRα3 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 GFRα3-like immunoreactivity. In the rat, GFRα3- 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 GFRα3- and RET-like staining, suggesting co-localization. In other tissues, sub-populations of cells expressed either GFRα3- or RET-like immunoreactivity. The functional consequences of GFRα3 expression in non-neural cells remain to be determined.
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References
Baloh RH, Gorodinsky A, Golden JP, Tansey MG, Keck CL, Popescu NC, Johnson EM Jr, Milbrandt J (1998) GFRalpha3 is an orphan member of the GDNF/neurturin/persephin receptor family. Proc Natl Acad Sci USA 95(10):5801–5806
Baloh RH, Tansey MG, Golden JP, Creedon DJ, Heuckeroth RO, Keck CL, Zimonjic DB, Popescu NC, Johnson EM Jr, Milbrandt J (1997) TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 18(5):793–802
Bennett DL, Michael GJ, Ramachandran N, Munson JB, Averill S, Yan Q, McMahon SB, Priestley JV (1998) A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci 18(8):3059–3072
Bolon B, Jing S, Asuncion F, Scully S, Pisegna M, Van GY, Hu Z, Yu YB, Min H, Wild K, Rosenfeld RD, Tarpley J, Carnahan J, Duryea D, Hill D, Kaufman S, Yan XQ, Juan T, Christensen K, McCabe J, Simonet WS (2004) The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction. Toxicol Pathol 32(3):275–294
Carmillo P, Dago L, Day ES, Worley DS, Rossomando A, Walus L, Orozco O, Buckley C, Miller S, Tse A, Cate RL, Rosenblad C, Sah DW, Gronborg M, Whitty A (2005) Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-1 (GFRalpha1)is highly selective for GDNF versus artemin. Biochemistry 44(7):2545–2554
Ehrenfels CW, Carmillo PJ, Orozco O, Cate RL, Sanicola M (1999) Perturbation of RET signaling in the embryonic kidney. Dev Genet 24(3–4):263–72
Gardell LR, Wang R, Ehrenfels C, Ossipov MH, Rossomando AJ, Miller S, Buckley C, Cai AK, Tse A, Foley SF, Gong B, Walus L, Carmillo P, Worley D, Huang C, Engber T, Pepinsky B, Cate RL, Vanderah TW, Lai J, Sah DW, Porreca F (2003) Multiple actions of systemic artemin in experimental neuropathy. Nat Med 9(11):1383–1389
Iwamoto T, Taniguchi M, Asai N, Ohkusu K, Nakashima I, Takahashi M (1993) cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Oncogene 8(4):1087–1091
Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, Delaney J, Schultz H, Zhou R, Fox GM (1997) GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem 272(52):33111–33117
Josephson A, Widenfalk J, Trifunovski A, Widmer HR, Olson L, Spenger C (2001) GDNF and NGF family members and receptors in human fetal and adult spinal cord and dorsal root ganglia. J Comp Neurol 440(2):204–217
Naveilhan P, Baudet C, Mikaels A, Shen L, Westphal H, Ernfors P (1998) Expression and regulation of GFRalpha3, a glial cell line-derived neurotrophic factor family receptor. Proc Natl Acad Sci USA 95(3):1295–1300
Orozco OE, Walus L, Sah DW, Pepinsky RB, Sanicola M (2001) GFRalpha3 is expressed predominantly in nociceptive sensory neurons. Eur J Neurosci 13(11):2177–2182
Pachnis V, Mankoo B, Costantini F (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119(4):1005–1017
Trupp M, Belluardo N, Funakoshi H, Ibanez CF (1997) Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret protooncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci 17(10):3554–3567
Walker DG, Beach TG, Xu R, Lile J, Beck KD, McGeer EG, McGeer P (1998) Expression of the proto-oncogene Ret, a component of the GDNF receptor complex, persists in human substantia nigra neurons in Parkinson’s disease. Brain Res 792(2):207–217
Widenfalk J, Nosrat C, Tomac A, Westphal H, Hoffer B, Olson L (1997) Neurturin and glial cell line-derived neurotrophic factor receptor-beta (GDNFR-beta), novel proteins related to GDNF and GDNFR-alpha with specific cellular patterns of expression suggesting roles in the developing and adult nervous system and in peripheral organs. J Neurosci 17(21):8506–8519
Widenfalk J, Tomac A, Lindqvist E, Hoffer B, Olson L (1998) GFRalpha-3, a protein related to GFRalpha-1, is expressed in developing peripheral neurons and ensheathing cells. Eur J Neurosci 10(4):1508–1517
Worby CA, Vega QC, Chao HH, Seasholtz AF, Thompson RC, Dixon JE (1998) Identification and characterization of GFRalpha-3, a novel Co-receptor belonging to the glial cell line-derived neurotrophic receptor family. J Biol Chem 273(6):3502–3508
Yu T, Scully S, Yu Y, Fox GM, Jing S, Zhou R (1998) Expression of GDNF family receptor components during development: implications in the mechanisms of interaction. J Neurosci 18(12):4684–4696
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We thank Ricardo Sanchez for technical assistance with tissue preparation and Dane Worley for technical discussions.
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Yang, C., Hutto, D. & Sah, D.W.Y. Distribution of GDNF family receptor α3 and RET in rat and human non-neural tissues. J Mol Hist 37, 69–77 (2006). https://doi.org/10.1007/s10735-006-9035-8
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DOI: https://doi.org/10.1007/s10735-006-9035-8