NRTN
Neurturin precursor
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Glial cell-line derived neurotrophic factor (GDNF) and related factors neurturin (NRTN), artemin, and persephin are members of the GDNF family of neurotrophic factors. GDNF and NRTN bind to the tyrosine kinase receptor Ret and the receptors GFRalpha1 and GFRalpha2. The objective was to examine the developmental expression of GDNF, NRTN, and their receptors within the rat urinary bladder. Rat bladders dissected from embryonic day (E) 15, postnatal day (P) 0, P14, P28, and adult rats (P60) were investigated by semiquantitative reverse transcriptase polymerase chain reaction. Embryos (E15, E16, and E17) were immunohistochemically stained for neurofilament. GDNF and Ret mRNA levels at E15 were the highest of all the stages we examined and then immediately decreased. In contrast, NRTN mRNA levels did not change between E15 and postnatal day 14; thereafter, they gradually but insignificantly increased. GFRalpha1 and GFRalpha2 mRNA levels were high at E15, after which their signal intensities decreased. In whole-mounted specimens, neurofilament-positive axons were first detected in the bladder at E16. Our results suggest that GDNF and NRTN may act as trophic factors for neural in-growth to the bladder and/or for the maintenance of mature neurons innervating the bladder. These factors might also be involved in bladder morphogenesis.
MeSH Terms
- Aging
- Animals
- Drosophila Proteins
- Embryonic and Fetal Development
- Fetus
- Glial Cell Line-Derived Neurotrophic Factor
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- Nerve Growth Factors
- Neurturin
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-ret
- RNA, Messenger
- Rats
- Receptor Protein-Tyrosine Kinases
- Receptors, Cell Surface
- Urinary Bladder
Neurturin (NRTN), signalling via the GDNF family receptor alpha2 (GFRalpha2) and Ret tyrosine kinase, has recently been identified as an essential target-derived factor for many parasympathetic neurons. NRTN is expressed in salivary and lacrimal glands, while GFRalpha2 and Ret are expressed in the corresponding submandibular, otic and sphenopalatine ganglia. Here, we have characterized in more detail the role of GDNF and NRTN signalling in the development of cranial parasympathetic neurons and their target innervation. Gfra1 mRNA was expressed at E12 but not in newborn cranial parasympathetic ganglia, while Gfra2 mRNA and protein were strongly expressed in newborn and adult cranial parasympathetic neurons and their projections, respectively. In newborn GFRalpha1- or Ret-deficient mice, where many submandibular ganglion neurons were still present, the otic and sphenopalatine ganglia were completely missing. In contrast, in newborn GFRalpha2-deficient mice, most neurons in all these ganglia were present. In these mice, the loss and atrophy of the submandibular and otic neurons were amplified postnatally, accompanied by complete loss of innervation in some target regions and preservation in others. Surprisingly, GFRalpha2-deficient sphenopalatine neurons, whose targets were completely uninnervated, were not reduced in number and only slightly atrophied. Thus, GDNF signalling via GFRalpha1/Ret is essential in the early gangliogenesis of some, but not all, cranial parasympathetic neurons, whereas NRTN signalling through GFRalpha2/Ret is essential for the development and maintenance of parasympathetic target innervation. These results indicate that GDNF and NRTN have distinct functions in developing parasympathetic neurons, and suggest heterogeneity among and within different parasympathetic ganglia.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Brain
- Drosophila Proteins
- Ganglia, Parasympathetic
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- In Situ Hybridization
- Mice
- Mice, Knockout
- Neurons
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-ret
- RNA, Messenger
- Receptor Protein-Tyrosine Kinases
- Signal Transduction
- Transcription, Genetic
The GDNF family of neurotrophic factors currently has four members: neurturin (NRTN), glial cell line-derived neurotrophic factor (GDNF), persephin, and artemin. These proteins are potent survival factors for several populations of central and peripheral neurons. The receptors for these factors are complexes that include the Ret tyrosine kinase receptor and a GPI-linked, ligand-binding component called GDNF family receptor alpha 1-4 (GFRalpha1-4). We have used in situ hybridization to study the mRNA expression of NRTN, GDNF, Ret, GFRalpha1, and GFRalpha2 during embryonic development and in the adult mouse. GDNF receptors were prominently expressed during embryonic development in the nervous system, the urogenital system, the digestive system, the respiratory system, and in developing skin, bone, muscle, and endocrine glands. In some regions, incomplete receptor complexes were expressed suggesting that other, as yet unidentified, receptor components exist or that receptor complexes are formed in trans. NRTN and GDNF were expressed in many trigeminal targets during embryonic development including the nasal epithelium, the teeth, and the whisker follicles. NRTN and GDNF were also expressed in the developing limbs and urogenital system. In the embryo, GDNF factors and receptors were expressed at several sites of mesenchyme/epithelial induction, including the kidney, tooth, and submandibular gland. This expression pattern is consistent with the possibility that the GDNF factors function in inductive processes during embryonic development and with the recently discovered role of NRTN as a necessary trophic factor for the development of some parasympathetic neurons. In the mature animal, receptor expression was more limited than in the embryo. In the adult mouse, NRTN was most prominently expressed in the gut, prostate testicle, and oviduct; GDNF was most prominently expressed in the ovary.
MeSH Terms
- Aging
- Animals
- Brain
- Drosophila Proteins
- Embryonic and Fetal Development
- Female
- Gene Expression Regulation, Developmental
- Glial Cell Line-Derived Neurotrophic Factor
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- In Situ Hybridization
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred ICR
- Nerve Growth Factors
- Nerve Tissue Proteins
- Neurturin
- Organ Specificity
- Peripheral Nervous System
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-ret
- RNA, Messenger
- Receptor Protein-Tyrosine Kinases
- Transcription, Genetic