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PubMed2001

Plant factors influencing enzyme retting of fiber and seed flax.

Retting, which is the microbial activity through which bast fibers are released from nonfiber tissues, is the limiting factor in flax processing. The objective of this work is to identify chemical and structural characteristics in a variety of fiber and seed flax types that influence enzyme retting in a recently developed method. Analyses of flax retted in a series of tests, including two enzyme rettings in some cases, indicated that lignin did not limit the separation of fibers from shive and showed that pectinases in enzyme-retting mixtures could ret fiber and seed flax. However, mature stems, such as that in flax produced for seed, had greater amounts of cutin and wax in the cleaned fiber product, suggesting that the cuticle could be a greater antiquality factor in seed versus fiber flax. With seed flax, the fraction of finer fibers produced during retting was significantly lower than with fiber flax. Results indicated that enzyme retting could be used to obtain flax fibers from seed flax stem residues and add value to this agricultural material.

Dietary Fiber↗
PubMed2001

Mutational analysis of the RET and GDNF gene in children with hypoganglionosis.

Germline mutations of the RET (10q11.2) have been reported in Hirschsprung's disease (HSCR) at a rate of 15-45%. Recently, the glial cell line-derived neurotrophic factor (GDNF) was identified as one of the ligands of the RET, and GDNF (5p12-p13.1) mutations were also found in association with RET mutations in HSCR patients. We analysed the DNA sequence of RET and the GDNF of patients with hypoganglionosis. We investigated the germline mutation in 5 patients histologically diagnosed with hypoganglionosis. DNAs were extracted from peripheral blood lymphocytes of these patients. The PCR primers were designed for RET tyrosine kinase domain (exon 13-17) and GDNF (exon 1-2). The DNA sequence was determined using a direct DyeDeoxy Terminator Cycle method. The analysis of RET showed silent mutation at the codon 769 (CTT-->CTG) by DNA polymorphism in all patients. No other mutation of the RET or GDNF was evident. These results suggest that the RET or GDNF may not contribute to the pathogenesis of hypoganglionosis, which is suspected to be genetically different from HSCR.

Child↗
PubMed1999

The RET receptor tyrosine kinase, but not its specific ligand, GDNF, is preferentially expressed by acute leukaemias of monocytic phenotype and is up-regulated upon differentiation.

The RET gene product represents the signal-transducing molecule of a surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), which includes GDNFR-alpha as a ligand-binding component. By a semi-quantitative competitive RT-PCR approach, we have analysed the relative abundances of RET transcripts in blasts purified from 40 acute myeloid leukaemia (AML) cases, revealing significant amounts of RET transcripts in 60% of AML cases (24/40). RT-PCR data was confirmed by immunocytochemical detection of RET protein in leukaemic blasts. The highest RET mRNA levels, almost exclusively confined to FAB M4/M5 AMLs, directly correlated with the presence on leukaemic cells of adhesion molecules and surface structures typically expressed by blasts of monocytic lineage and were inversely associated with the expression of the stem cell antigen CD34. Consistently, differentiation of the monoblastic cell line U937 resulted in an up-regulated expression of RET proto-oncogene, which was maximal upon exposure to agents inducing a more complete monocytic differentiation. Finally, while transcripts specific for GDNF and GDNFR-alpha were never found in leukaemic blasts, stromal cells of the haemopoietic microenvironment expressed, in the absence of RET, significant amounts of both GDNF and GDNFR-alpha. Our results suggest a role for RET in the functional regulation of AMLs through interactions with GDNF- and GDNFR-alpha-producing stromal cells.

Bone Marrow Cells↗
PubMed1993

RET-PE10: a 61 kD polypeptide epitope expressed late during vertebrate RPE maturation.

PURPOSE: This study sought To learn more about the mechanisms that determine and maintain the differentiated state of the retinal pigment epithelium (RPE). METHODS: Monoclonal antibodies were raised against human RPE and used in conjunction with other antibodies. Immunocytochemical and biochemical analyses were performed on tissue sections and cells in culture. RESULTS: An RPE-specific epitope, RET-PE10, has been detected as a 61 kD cytoplasmic polypeptide in a variety of mammalian, amphibian, and avian species. In the rat, RPE-PE10 was expressed late in eye development, with a faint initial labelling of the RPE in central regions at postnatal day 9 (PN9) that increased to adult levels and extent of staining by PN14. RET-PE10 expression initially was present in overnight cultures of dissociated rat RPE cells but was lost rapidly from these cultures during the first week. Comparison of the staining patterns of RET-PE10 with those of various cytoskeletal elements suggests that RET-PE10 may be associated with part of the intermediate filament network. Culture of whole eyecups also resulted in a loss of RET-PE10 expression. RET-PE10 expression was normal in eyes of adult rd/rd mutant mice. CONCLUSIONS: RET-PE10 is a late-appearing marker of RPE differentiation. The results also suggest that the maintained expression of RET-PE10 depends upon extrinsic factors but that these do not include maintained contact with Bruch's membrane or light-induced retinal activity.

Animals↗
PubMed1994

Developmental expression of the RET protooncogene.

The RET protooncogene encodes a transmembrane protein of the receptor-type tyrosine kinase family whose ligand has not yet been identified. Its activation in vivo is restricted to human carcinomas of the thyroid. In order to learn more about the possible role played by RET during normal development, we have examined its expression by performing in situ hybridization experiments on mouse embryos. Here, we show that the RET protooncogene is expressed during mouse embryogenesis in an unusual temporal and spatial manner. In fact, its expression was first detected around day 10 of gestation in the basal plate of the neural tube and in the developing encephalic ganglia, and later its pattern of expression was definitely established in neural structures, mostly in neural crest derivatives (spinal and encephalic ganglia). As far as the central nervous system is concerned, RET expression was confined to the ventral part of the midbrain from 12.5 days postcoitum (dpc) until birth. RET was also found to be expressed within structures of sensory organs such as the ganglial layer of the retina and the olfactory epithelium. A peculiar pattern of RET expression was clearly observed in the wall of the gut and in the nephrogenic zone of the developing kidney cortex, specifically in the metanephrogenic vesicles. Finally, RET was found to be expressed in the liver mostly between 12.5 dpc and 14.5 dpc. In conclusion, its expression in the early stages of embryogenesis suggests that RET may play a role in the differentiation of specific neural structures and the excretory system.

Animals↗
PubMed1998

The fetal origin of B-precursor leukemia in the E-mu-ret mouse.

Before the clinical onset of B-precursor lymphoblastic leukemia, E-mu-ret mice have an expansion of late pro-B cells (CD45R+CD43(+)CD24(+)BP-1(+)) within the bone marrow. To characterize the early effects of the transgene product on lymphopoiesis, we initially sequenced the Ig heavy chain (IgH) rearrangements within the late pro-B cells in 24-day-old E-mu-ret and transgene negative mice. In both mouse populations, the IgH rearrangements were polyclonal, predominately nonproductive, and exhibited similar V, D, and J gene usage. However, the frequency of N regions, a marker of postnatal lymphopoiesis, was notably different. At the VD junction, N regions were found in 25 of 25 (100. 0%) rearrangements from transgene-negative mice compared with 12 of 36 (33.3%) rearrangements from Emicro-ret mice. At the DJ junction, N regions were found in 21 of 25 (84.0%) rearrangements from transgene negative mice compared with 4 of 36 (11.1%) rearrangements from E-mu-ret mice. Subsequently, we sequenced the clonal IgH rearrangements from 9 leukemias that developed in 10-to 38-week-old mice and found that 7 leukemias had a least 1 rearrangement that lacked N regions at the DJ junction. In addition, V replacement events were observed in the 1 leukemia studied in detail. Terminal deoxynucleotidyl transferase, the enzyme responsible for N region addition, was expressed at markedly lower levels in late pro-B cells from 7- to 10-day-old E-mu-ret mice compared with transgene-negative mice. Examination of fetal lymphopoiesis in E-mu-ret mice identified a relative increase in early (CD45R+CD43(+)CD24(+)BP-1(-)) and late pro-B cells and a decrease in more differentiated CD43(-) B-lineage cells. Fetal early pro-B cells from Emicro-ret mice proliferated threefold to fivefold greater but differentiated to a lesser extent than those from transgene negative mice when cultured in vitro with interleukin-7. These data suggest that the B precursor leukemias in adult E-mu-ret mice arise from the progeny of pro-B cells generated in utero.

Animals↗
PubMed1998

Expression of the RET proto-oncogene in human embryos.

The patterns of RET proto-oncogene expression in mouse, rat, and chicken and the anomalies observed in targeted RET mutants suggest that RET plays a major role in development of mouse enteric nervous system and in kidney organogenesis. Here, we report on in situ hybridization studies describing the pattern of RET proto-oncogene expression during early development of human embryos between 23 and 42 days. We show that the RET gene is expressed in the developing kidney (nephric duct, mesonephric tubules, and ureteric bud), the presumptive enteric neuroblasts of the developing enteric nervous system, cranial ganglia (VII+VIII, IX, and X) and in the presumptive motor neurons of the spinal cord. Yet, despite the high level of RET gene expression in the kidney and in the motor neurons of the developing central nervous system in human embryos, only rare cases with renal agenesis have been reported in Hirschsprung disease patients, and no clinical evidence of spinal cord involvement has been shown in patients carrying RET germline mutations (i.e., multiple endocrine neoplasia syndromes and Hirschsprung disease).

Central Nervous System↗
PubMed1998

Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms?

Despite the large amount of information accumulated on the role played by ret activation in the oncogenesis of papillary thyroid carcinoma (PTC), the biological and clinical significance of such activation 'in vivo' remains controversial. The aim of this study was to address some of the existing controversies by comparing two groups of unselected PTCs, one with and the other without ret rearrangement, with regard to several clinicopathological and biological features. Thirty-three PTCs were selected at random. ret rearrangement was found in eight cases (24.2 per cent) using Southern blot analysis. The mean age of the patients with tumours displaying ret rearrangement (28 +/- 3.1 years) was significantly lower than that of the patients harbouring cases that did not present rearrangement (45 +/- 2.9 years). The large majority of the tumours with ret rearrangement displayed a papillary or mixed follicular-papillary pattern and very low proliferative activity. ret rearrangement correlated significantly with decreased cytoplasmic expression of E-cadherin. No significant differences were found regarding the gender of the patients, tumour size, multicentricity, extrathyroidal growth, vascular invasion, lymphocytic infiltration, lymph node involvement or the expression of E-cadherin (membrane), c-erb-B2, c-met, Bcl-2, and vimentin. It is proposed that sporadic PTCs harbouring a ret rearrangement occur frequently as slow growing, papillary, or predominantly papillary tumours that do not usually progress towards less differentiated neoplasms representing what might be described as a Bonsai phenotype.

Adolescent↗
PubMed2000

RET is expressed but not mutated in extra-adrenal paragangliomas.

This study has investigated the role of the RET proto-oncogene, which has been identified as the susceptibility gene for multiple endocrine neoplasia (MEN) type 2, in the development of sporadic and familial extra-adrenal paragangliomas. RET protein expression was analysed by immunohistochemistry. Subsequently, DNA extracted from 52 tumours of 44 patients was screened for somatic RET point mutations in exons 10, 11, and 13-16, where oncogenic mutations have recently been described in a subset of sporadic medullary thyroid carcinomas and phaeochromocytomas. The methods employed included non-isotopic polymerase chain reaction-based single strand conformation polymorphism (PCR-SSCP) analysis and heteroduplex gel electrophoresis, followed by direct sequencing of PCR products. RET protein expression was demonstrated in all ten paragangliomas tested. However, none of the familial or sporadic extra-adrenal paragangliomas contained somatic mutations in exons 10, 11, or 13-16 of the RET proto-oncogene, whereas control samples with known mutations in these exons exhibited the expected band shift, or yielded an additional band with retarded migration. Although paragangliomas exhibit RET protein expression, these data indicate that oncogenic RET proto-oncogene mutations do not appear to be generally important in the formation of sporadic paragangliomas.

Adult↗
PubMed2001

Evidence for a ligand-specific signaling through GFRalpha-1, but not GFRalpha-2, in the absence of Ret.

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two homologeous proteins that have been recognized as potent survival factors for distinct neuronal populations. GDNF and NTN act through a two-component receptor system consisting of the ligand-specific binding subunits GDNF family receptor (GFR)alpha-1 and GFRalpha-2 and the common transducing subunit c-Ret. In addition, it has been demonstrated that GDNF can signal through GFRalpha-1 in the absence of c-Ret. In the present study, we sought to determine whether a similar c-Ret-independent signaling applies for GFRalpha-2. In addition, we have characterized the ligand specificity of the c-Ret-independent action of GFRalphas. To establish an assay system for these studies, several neural cell lines were screened for the presence of GDNF and NTN receptor subunits by RT-PCR and immunoblot analysis. c-Ret expression was detectable only in Neuro2A cells, which did not express GFRalpha-1 or GFRalpha-2. The neuronal cell line LS expressed GFRalpha-2, and the glial cell line Mes42 expressed GFRalpha-1, whereas the neuronal cell line B104 expressed both GFRalpha-1 and GFRalpha-2. Stimulation of B104 and Mes42 cells with GDNF, but not with NTN, for 10 min resulted in CREB phosphorylation. In apparent contrast, neither NTN nor GDNF promoted CREB activation in LS and Neuro2A cells. Moreover, exposure of LS cells to NTN or GDNF also failed to activate AKT and ERK. Together these findings provide evidence that, in contrast to GFRalpha-1, GFRalpha-2 fails to signal in the absence of c-Ret. In addition, these observations reveal that c-Ret-independent signaling of GFRalpha-1 is ligand- specific and occurs only with GDNF.

Animals↗
PubMed1998

Multiple GPI-anchored receptors control GDNF-dependent and independent activation of the c-Ret receptor tyrosine kinase.

Glial cell line-derived neurotrophic factor (GDNF) mediates neuronal survival through a receptor complex composed of the c-Retproto-oncogene and GFR alpha-1, a member of a family of GPI-anchored receptors. The extent of cross-talk between GDNF and GFR alpha receptors and its possible significance for c-Ret activation is presently unclear. Using chemical crosslinking we demonstrate here a specific interaction between GDNF and GFR alpha-2 expressed in COS cells, albeit of a lower affinity than the one between GDNF and GFR alpha-1. In addition, GFR alpha-2 mediated crosslinking of GDNF of c-Ret as well as ligand-dependent stimulation of c-Ret tyrosine phosphorylation. We also describe the isolation of a novel, more divergent member of the GFR alpha family, GFR alpha-3, which did not bind GDNF directly, but was able to mediate crosslinking of GDNF to c-Ret when both receptors were coexpressed in COS cells. Thus, all three GFR alpha receptors mediate GDNF binding to c-Ret with efficiencies GFR alpha-1 > GFR alpha-2 > GFR alpha-3. c-Ret showed high levels of constitutive tyrosine autophosphorylation upon overexpression in COS cells, which was inhibited in a dose-dependent manner by coexpression with any of the GFR alpha receptors, suggesting that GFR alpha s may also provide a gain control mechanism to increase the signal-to-noise ratio of the response to ligand. GFR alpha-2 showed a dynamic pattern of expression in rat brain, distinct from that of GFR alpha-1, characterized by high expression in cortex, basal forebrain, and specific layers of the olfactory bulb, and low or no expression in substantia nigra, cerebellum, and motor nuclei. GFR alpha-2, but not GFR alpha-3 mRNA expression was highly induced in several nuclei after stimulation with kainic acid. In contrast to GFR alpha-1 and GFR alpha-2, GFR alpha-3 expression in postnatal and adult brain was highly restricted. Developmentally regulated expression of GFR alpha-3 was, however, detected in several peripheral organs and ganglia. Together, these results indicate complementary roles for GFR alpha receptors in the regulation of c-Ret activity and the maintenance of distinct neuronal circuits in the central and peripheral nervous systems.

Amino Acid Sequence↗
PubMedDate not supplied

Ret-proto-oncogene analysis in medullary thyroid carcinoma.

INTRODUCTION: Medullary carcinoma of the thyroid (MTC) is a rare tumour which occurs in both sporadic and hereditary forms. Mutations of the RET proto-oncogene have been identified in hereditary forms. The aim of our study was to confirm or exclude familial disease by examining for germline mutations in the RET proto-oncogene in patients with medullary thyroid carcinoma. METHODS: Nine patients with medullary thyroid carcinoma and 4 of their children were studied. Peripheral blood was used to examine for mutations in the RET proto-oncogene. When this was not available, archival thyroid tissue was used. RESULTS: Seven patients had clinically sporadic tumours confirmed by mutational analysis of RET. Four children were at risk of being carriers of a mutated gene, as their fathers had histologically proven MTC and had tested positive for the mutation at codon 618 on exon 10 of the RET proto-oncogene. Three of these children carried the 618 mutation. To date, 2 have had a prophylactic thyroidectomy, the pathology of which revealed C-cell hyperplasia. One child had familial disease excluded by mutational analysis. One patient had a clinical diagnosis of MEN2B confirmed by detection of the 918 mutation on exon 16 of the RET proto-oncogene. CONCLUSIONS: RET proto-oncogene analysis is a reliable method of differentiating familial from sporadic MTC. Mutational information determines which family members of affected kindreds are at risk of developing the disease and can be used to affect clinical management.

Adolescent↗
PubMed2005

Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg.

Familial medullary thyroid carcinoma (FMTC) is an autosomal dominant inherited disease, characterized by germ-line mutations in the RET proto-oncogene, mainly in exons 10 and 11, but also in exons 13, 14 and 15. Recently, mutations in exons 8 and 16 associated with FMTC were also described. In the herein presented study, single strand conformation polymorphism (SSCP) method for rapid screening of mutations in the RET proto-oncogene and fluorescent sequencing method were used. In one Czech family with FMTC, we have identified a novel missense point mutation of the RET proto-oncogene in exon 5, that results in substitution of arginine by glycine at codon 321 in the cadherin-like domain of ret protein. It seems that this mutation causes FMTC as no other mutation was found in the classical risk exons (10, 11, 13, 14, 15 and 16) of the RET proto-oncogene. The mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in two patients; two other family members are mutation carriers without clinical signs of MTC so far. To improve the diagnosis of FMTC, analysis of exon 5 of the RET proto-oncogene should be considered in families with no identified classical RET mutations.

Adult↗
PubMed1997

Absence of mutations in the RET gene in acute myeloid leukemia.

Expression of the tyrosine kinase receptor RET has previously been detected in normal hematopoietic cells, and especially in cells of the myeloid lineage. Furthermore, RET was shown to be differentially expressed in acute myeloid leukemia (AML), a disease characterized by excessive cell growth and aberrant maturation of cells, with the highest levels of expression in leukemias with monocytic differentiation. RET is known to be expressed in cells from the excretory system and from the developing central and peripheral nervous system. Both activating and inactivating aberrations in the RET gene have been detected in disorders derived from these tissues. To investigate whether the differential expression is a primary defect in AML, the presence of RET alterations was scanned by Southern blot analysis on DNA of blasts obtained from 17 AML patients. However, no RET gene aberrations were found. Subsequently, denaturing gradient gel electrophoresis (DGGE) analysis was performed on the DNA of blasts from ten selected cases. All five variants detected turned out to represent neutral DNA polymorphisms, including a novel polymorphism in exon 14. Since we were unable to detect mutations of RET in AML, it is unlikely that it plays an important role in leukemogenesis.

Blotting, Southern↗
PubMedDate not supplied

RET(Men2B)-transgene produces sympathoadrenal tumors but does not prevent intestinal aganglionosis in gdnf-/- or gfr alpha-1(-/-) mice.

Multiple endocrine neoplasia type 2B (MEN2B) syndrome is caused by a missense mutation in the RET gene, which replaces Met918 by Thr in the intracellular kinase domain of the protein. This single amino acid substitution transforms the receptor into a constitutively active monomeric kinase (RET(Men2B)) and produces an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies, and mucosal ganglioneuromas. The ligand, GDNF, stimulates RET activity through a co-receptor, GFR alpha-1. In vitro studies have shown that the kinase and mitogenic properties of RET(Men2B) are enhanced by GDNF/GFR alpha-1 stimulation. A relevant clinical question is whether ablation of either GDNF or GFR alpha-1 could alter penetrance or severity of the MEN2B syndrome. We report that ganglioneuromatous tumors caused by a RET(Men2B) transgene in mice are not affected grossly or microscopically by the absence of gdnf or gfr alpha-1. Loss-of-function mutations in ret, gdnf, or gfr alpha-1 cause pan-intestinal aganglionosis in mice. We find that expression of the RET(Men2B) transgene in enteric neural progenitors, after they colonize the gut, does not prevent intestinal aganglionosis associated with gdnf or gfr alpha-1 deficiency.

Acetylcholinesterase↗
PubMed1996

Proto-RET is rearranged in the new human papillary thyroid cancer cell line PTC-1113A.

The receptor tyrosine kinase proto-RET is believed to contribute to thyroid oncogenesis by activation of its tyrosine kinase either by point mutation or rearrangement. The papillary thyroid cancer cell lines PTC-1113A, L, and R were established from a recurrent thyroid cancer and its metastases. The rearrangement of the proto-ret oncogene in the cell line PTC-1113A is demonstrated by Southern analysis utilizing the probe for rearranged ret that encodes the fusion protein H4/tyrosine kinase. In contrast, rearranged ret alleles were not found in the cell lines that developed from metastases, nor in DNA isolated from the recurrent tumor. The cell line PTC-1113A may represent a population of tumor cells that gained a growth advantage due to rearranged ret. This is the second human thyroid cancer cell line harboring rearranged ret, and may serve to study the function of ret activation in thyroid cancers.

Drosophila Proteins↗
PubMed1995

Postmigratory neural crest cells expressing c-RET display restricted developmental and proliferative capacities.

c-RET is an orphan receptor tyrosine kinase essential for enteric neurogenesis in mice and is involved in several human genetic disorders. RET is also one of the earliest surface markers expressed by postmigratory neural crest cells in the gut. We generated anti-RET monoclonal antibodies to isolate such cells. We find that RET+ cells are antigenically and functionally distinct from neural crest stem cells (NCSCs) characterized previously. Unlike NCSCs, which are RET- and MASH1-, most RET+ cells express MASH1. Moreover, unlike NCSCs, which are multipotent and have high proliferative capacity, many RET+ cells generate only neurons following a limited number of divisions. This behavior is observed even in the presence of glial growth factor, a polypeptide that suppresses neuronal and promotes glial differentiation by NCSCs. These data provide direct evidence for the existence of committed neuronal progenitor cells and support a model of neural crest lineage diversification by progressive restriction of developmental potential.

Animals↗
PubMed2004

Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex.

The glial-cell-line-derived neurotrophic factor (GDNF) ligand activates the Ret receptor through the assembly of a multiprotein complex, including the GDNF family receptor alpha1 (GFRalpha1) molecule. Given the neuroprotective role of GDNF, there is an obvious need to precisely identify the structural regions engaged in direct interactions between the three molecules. Here, we combined a functional approach for Ret activity (in PC12 cells) to cross-linking experiments followed by MS-MALDI to study the interactions among the purified extracellular region of the human Ret, GDNF and GFRalpha1 molecules. This procedure allowed us to identify distinct regions of Ret that are physically engaged in the interaction with GDNF and GFRalpha1. The lack of these regions in a recombinant Ret form results in the failure of both structural and functional binding of Ret to GFRalpha1/GDNF complex. Furthermore, a model for the assembly of a transducing-competent Ret complex is suggested.

Animals↗