Disease relevance of Ret

• Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb [1].
• In newborn GFRalpha1- or Ret-deficient mice, where many submandibular ganglion neurons were still present, the otic and sphenopalatine ganglia were completely missing [2].
• Germ line mutations of the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2A (MEN 2A), an inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia [3].
• Multiple endocrine neoplasia 2A (MEN 2A) is an inherited disease caused by mutations of the Ret proto-oncogene [4].
• Rara(-/-) Rarb2(-/-) mice display impaired vitamin A signaling and develop syndromic urogenital malformations similar to those that occur in humans, including renal hypoplasia, hydronephrosis and mega-ureter, abnormalities also seen in mice with mutations in the proto-oncogene Ret [5].

Psychiatry related information on Ret

• We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients [1].

High impact information on Ret

• Here we show that ureter maturation depends on formation of the 'trigonal wedge', a newly identified epithelial outgrowth from the base of the Wolffian ducts, and that the distal ureter abnormalities seen in Rara(-/-) Rarb2(-/-) and Ret(-/-) mutant mice are probably caused by a failure of this process [5].
• Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret [5].
• Our studies indicate that formation of the trigonal wedge may be essential for correct insertion of the distal ureters into the bladder, and that these events are mediated by the vitamin A and Ret signaling pathways [5].
• In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning [6].
• Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A-dependent signals secreted by stromal cells control Ret expression in the ureteric bud [6].

Chemical compound and disease context of Ret

• Ret, the GDNF receptor tyrosine kinase, was upregulated in podocytes in the passive Heymann nephritis and puromycin aminonucleoside (PA) nephrosis rat models of podocyte injury [7].
• Although several familial medullary thyroid carcinoma and most MEN2A mutations involve substitutions of extracellular cysteine residues, in most MEN2B cases there is a methionine-to-threonine substitution at position 918 (M918T) of the Ret kinase domain [8].
• Advantages of the mouse lines include expression of substantial levels of the epinephrine-synthesizing enzyme, phenylethanolamine N-methyltransferase and expression of high levels of the receptor tyrosine kinase, Ret, which is characteristic of sporadic and familial human pheochromocytomas but not of PC12 cells [9].
• The ret/PTC oncogene, a rearranged form of the ret proto-oncogene, has been found to be restricted to human papillary thyroid carcinomas [10].
• No mutations of the RET proto-oncogene including the cysteine-rich region or codon 768 and 918 in the tyrosine kinase domain were detected in 172 human pituitary adenomas either by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) or by PCR-restriction fragment length polymorphism (RFLP) [11].

Biological context of Ret

• In addition, two independently generated loss-of-function alleles of murine Ret, Ret.k- and miRet51, result in characteristic defects of neural crest cell migration within the developing gut [12].
• Members of the GDNF family, which are important during peripheral nervous system development and kidney organogenesis, signal via Ret and GFRalpha receptors [13].
• We used the whole-testis transplantation technique to overcome the limitation of neonatal lethality of Gdnf-, Gfra1-, and Ret-deficient mice and found that each of these genes is required for postnatal spermatogenesis and not for embryological testes development [14].
• Although many different Ret mutations have been described, little is known about the signaling pathways triggered by the Ret oncogene [4].
• Targeted mutagenesis in transgenic mice has shown that Ret, GFR alpha 1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease [15].

Anatomical context of Ret

• In the anlagen of the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression [16].
• Fibroblasts expressing TrnR2 and Ret are approximately 30-fold more sensitive to NTN than to GDNF treatment, whereas those expressing TrnR1 and Ret respond equivalently to both factors, suggesting the TrnR2-Ret complex acts preferentially as a receptor for NTN [17].
• TrnR2 and Ret are expressed in neurons of the superior cervical and dorsal root ganglia, and in the adult brain [17].
• The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells [18].
• To clarify the role of Ret signaling components in enteric nervous system (ENS) development, we evaluated ENS anatomy and intestinal contractility in mice heterozygous for Ret, GFRalpha1 and Ret ligands [19].

Associations of Ret with chemical compounds

• Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase [20].
• Furthermore, we show that Ret is able to associate with the SH2 domain of Src in a phosphotyrosine-dependent fashion [21].
• The presence of Ret protein was confirmed in adult dopamine neurons using immunohistochemistry [22].
• Vitamin A controls epithelial/mesenchymal interactions through Ret expression [6].
• Here we investigated the role of the Ret gene, which encodes a transmembrane tyrosine kinase receptor, in the maturation of norepinephrine and respiratory systems [23].

Physical interactions of Ret

• Recombinant Crx binds in vitro not only to the Ret 4 site but also to the Ret 1 and BAT-1 sites [24].
• Phosphorylated Y1062 is part of a Ret multiple effector docking site that mediates recruitment of the Shc adapter and of phosphatidylinositol-3 kinase (PI3K) [8].

Enzymatic interactions of Ret

• Dok-4 could also be phosphorylated by the receptor tyrosine kinase Ret but not by platelet-derived growth factor receptor-beta or IGF-IR [25].

Regulatory relationships of Ret

• Furthermore, we show that Ret9 but not Ret51 induces epithelial cells to form branched tubular structures in three-dimensional cultures in a Shank3-dependent manner [18].
• We also measured the levels of Src kinase activity in cell lines expressing isoforms of the Ret receptor activated by different mutations [21].
• However, few chromaffin cells in Mash1(-/-) mice become PNMT positive and downregulate neurofilament and Ret expression [26].
• In vitro, GDNF supports the survival of small neurons that express Ret and bind IB4 while failing to support the survival of neurons expressing TrkA and CGRP [27].
• To study the differential activities of the two RET isoforms further, we generated transgenic mice expressing ligand-dependent and constitutively active forms of RET9 or RET51 under the control of the Hoxb7 regulatory sequences [28].

Other interactions of Ret

• Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching [29].
• Only mild reductions in neuron size and neuronal fiber counts occur in Ret(+/-) and Gfra1(+/-) mice [19].
• Ret-mediated mitogenesis requires Src kinase activity [21].
• Ret and p75 have also been reported to label migratory-stage enteric neuron precursors [30].
• We conclude that the neural crest cell population that arises from the vagal level of the neural axis and that populates the stomach, midgut, and hindgut expresses Phox2b, Ret, and p75 [30].

Analytical, diagnostic and therapeutic context of Ret

• Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb [1].
• Microinjection of a kinase inactive mutant of c-Src blocked Ret-mediated mitogenic effect [21].
• The location and sequence of appearance of enteric neuron precursors deduced from the explants grown under the kidney capsule or in organ culture was very similar to that seen with the Phox2b, Ret, and p75 antisera [30].
• Analysis of the tissue distribution of GFRalpha-1, GFRalpha-2, GFRalpha-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression [31].
• Western blot analysis showed that proto-Ret proteins are expressed as 140-kDa and 160-kDa glycoproteins in Neuro-2a cells [32].

References