Biomedical subjects

E Winterhager

Publications and source records attributed to E Winterhager.

At least 37 records · Page 2Linked to original sources

PubMed2000

Expression of the imprinted genes MEST/Mest in human and murine placenta suggests a role in angiogenesis.

In the mouse fetus, Mest is widely expressed in mesoderm derived tissues. In separate studies in mice and in humans, it has been shown to be maternally imprinted, that is, only the paternally inherited allele is active. Here, we show that starting with implantation, Mest is also expressed in maternal decidua of the mouse and in placenta of both humans and mice. Expression in murine decidua was restricted to endothelial cells. After Day 7, expression in the decidua gradually decreased. Mest-specific RT-PCR and restriction fragment length variant (RFLV) analysis of decidualized endometrium isolated from (M. musculus x M. spretus)F1 females showed that only the paternally derived Mest allele was activated in the decidual endothelium. In the mouse extraembryonic tissues, Mest transcripts were detected in derivatives of extraembryonic mesoderm only. Here, hemangioblast precursor cells and endothelial cells were positive. At all developmental stages of the mouse, trophoblast-derived cells were clearly devoid of Mest transcripts. In the human placenta MEST transcripts were also detected in hemangioblast precursor cells, however, MEST was also expressed in villous and invasive cytotrophoblast. In a human choriocarcinoma/trophoblastic tumour grown in a nude mouse, human MEST was expressed in the tumour cells, whereas murine Mest was expressed in endothelia of the murine capillaries. The expression pattern exhibited by both Mest and MEST in extraembryonic tissues during development and during formation of choriocarcinoma/trophoblast tumour suggests a functional role of the MEST proteins related to oncofetal angiogenesis. Dev Dyn 2000;217:1-10.

Animals↗

PubMed2000

Reduced proliferation and cell adhesion in endometriosis.

Endometriosis is defined as endometriotic tissues growing outside the uterine cavity. The cell biological processes responsible for the pathogenesis of this disease are not well understood. In order to detect differences in proliferative activity between endometria and endometriotic lesions, Ki67 staining was analysed. In addition, expression of epidermal growth factor (EGF) and its receptor was examined using immunohistochemistry. For dedifferentiation processes pointing to invasive properties of the uterine epithelium, the presence of the adhesion complex E-cadherin with the associated alpha- and beta-catenin was investigated. Specimens of endometrium in the proliferative phase of 36 patients without, and 79 patients with, endometriosis together with endometriotic lesions were studied. The study revealed a significantly reduced proliferation activity in uterine epithelium within the ectopic lesions but no differences between eutopic endometria of non-affected and affected patients. Furthermore, a lower expression of both EGF and its receptor in the epithelial cells of the ectopic glands was observed. The adhesion complex E-cadherin, together with alpha-, and beta-catenin, was slightly reduced in uterine epithelial cells of women with endometriosis and less expressed in endometriotic lesions. The results indicate that epithelial cells of endometriotic lesions are not hyperproliferative, but do appear to dedifferentiate, displaying an invasive character.

Adult↗

PubMed2000

Defective vascular development in connexin 45-deficient mice.

In order to reveal the biological function(s) of the gap-junction protein connexin 45 (Cx45), we generated Cx45-deficient mice with targeted replacement of the Cx45-coding region with the lacZ reporter gene. Heterozygous Cx45(+/)(-) mice showed strong expression of the reporter gene in vascular and visceral smooth muscle cells. Cx45-deficient embryos exhibited striking abnormalities in vascular development and died between embryonic day (E) 9.5 and 10.5. Differentiation and positioning of endothelial cells appeared to be normal, but subsequent development of blood vessels revealed impaired formation of vascular trees in the yolk sac, impaired allantoic mesenchymal ingrowth and capillary formation in the labyrinthine part of the placenta, and arrest of arterial growth, including a failure to develop a smooth muscle layer surrounding the major arteries of the embryo proper. As a consequence, the hearts of most Cx45-deficient embryos were dilated. The abnormal development of the vasculature in the yolk sac of Cx45(-)(/)(-) embryos could be caused by defective TGFbeta signalling, as the amount of TGF beta1 protein in the epithelial layer of the yolk sac was largely decreased in the E9.5 Cx45(-)(/)(-) embryo, compared with the wild-type embryo. The defective vascular development was accompanied by massive apoptosis, which began in some embryos at E8.5 and was abundant in virtually all tissues of the embryos at E9.5. We conclude that in Cx45(-)(/)(-) embryos, vasculogenesis was normal, but subsequent transformation into mature vessels was interrupted. Development of different types of vessels was impaired to a varying extent, which possibly reflects the complementation by other connexin(s).

Aging↗

PubMed2000

E- and P-selectin expression in endometriotic tissues and the corresponding endometria.

Endometriosis is one of the most frequent diseases in gynecology. It is histologically defined as a non-malignant pathology in which endometrial-like tissue is found outside the uterus. The pathogenesis and mechanisms involved in the development of endometriosis-associated pain symptoms are still under investigation. A local peritoneal inflammation seems to play an important role in the origin of these symptoms. Selectins belong to a group of cell adhesion molecules that mediate the localization of circulating leukocytes on the endothelium at the sites of inflammation. The aim of this study was to investigate the expression of E- and P-selectins in endometriotic tissues and the corresponding endometria. Thirty endometriotic samples, 13 corresponding endometria and six endometria of patients without endometriosis were analyzed using an immunohistochemical technique. Just two endometriotic tissues expressed E-selectin, while five samples were positive for P-selectin. The selectin expression of the corresponding endometria was also very weak. No correlations between the revised American Fertility Society (rAFS) score or the hormonal situation of the patients at the time of biopsy and the selectin expression could be found. In conclusion, the selectin expression in endometriotic glands does not play an important role in the initiation of inflammatory processes caused by endometriosis. This inflammation must be considered as a secondary reaction after the implantation of the endometriotic glands, so that endometriotic tissues are not able to induce, by the expression of selectins, a direct inflammation.

Biopsy↗

PubMed1999

Transfection with different connexin genes alters growth and differentiation of human choriocarcinoma cells.

To examine the role of cell-cell communication via gap junctions in controlling proliferation and differentiation we transfected the malignant trophoblast cell line Jeg-3, which exhibits extremely low cell-cell communication mediated by endogenously expressed connexin40, with connexin26, connexin40, and connexin43, respectively. In vitro growth of all cell clones transfected with connexin genes was significantly reduced compared to controls. This effect corresponded to a significant increase in total junctional conductance of all clones. Single-channel conductances for channels formed by the transfected connexins were in the range of the values published previously. Though total junctional conductance varied highly among clones and even within one clone, differentiation of the cells indicated by beta-hCG secretion was most prominent in the clones that revealed the largest amount of well-coupled cell pairs. Connexin26 channels enable cells of one clone to reduce drastically growth rate and produce significantly higher secretion of beta-hCG. Connexin43 had only moderate effects on the differentiation properties of Jeg-3 cells. These findings suggest that restoration of cell-cell communication plays a role in growth reduction and in differentiation of tumor cells and that different channel proteins might have different effects.

Cell Communication↗

PubMed1999

Doubly mutant mice, deficient in connexin32 and -43, show normal prenatal development of organs where the two gap junction proteins are expressed in the same cells.

The connexins are a family of proteins that form the intercellular membrane channels of gap junctions. Genes encoding 13 different rodent connexins have been cloned and characterized to date. Connexins vary both in their distribution among adult cell types and in the properties of the channels that they form. In order to explore the functional significance of connexin diversity, several mouse connexin-encoding genes have been disrupted by homologous recombination in embryonic stem cells. Although those experiments have illuminated specific physiological roles for individual connexins, the results have also raised the possibility that connexins may functionally compensate for one another in cells where they are coexpressed. In the present study, we have tested this hypothesis by interbreeding mice carrying null mutations in the genes (Gjb1 and Gja1) encoding connexin32 (beta 1 connexin) and connexin43 (alpha 1 connexin), respectively. We found that fetuses lacking both connexins survive to term but, as expected, the pups die soon thereafter from the cardiac abnormality caused by the absence of connexin43. A survey of the major organ systems of the doubly mutant fetuses, including the thyroid gland, developing teeth, and limbs where these two connexins are coexpressed, failed to reveal any morphological abnormalities not already seen in connexin43 deficient fetuses. Furthermore, the production of thyroxine by doubly mutant thyroids was confirmed by immunocytochemistry. We conclude that, at least as far as the prenatal period is concerned, the normal development of those three organs in fetuses lacking connexin43 cannot simply be explained by the additional presence of connexin32 and vice-versa. Either gap junctional coupling is dispensable in embryonic and fetal cells in which these two connexins are coexpressed, or coupling is provided by yet another connexin when both are absent.

Alleles↗

PubMed1999

Developmental expression patterns of connexin26 and -30 in the rat cochlea.

Connexin proteins form transmembranous gap junction channels that connect adjacent cells. Connexin26 and connexin30 have been previously shown to be strongly expressed in the inner ear of adult rats and to be mainly colocalized. Because intercellular connections by gap junction proteins are crucial for maturation of different tissues, we investigated the developmental expression of connexin26 and connexin30 in pre- and postnatal rats using immunocytochemistry. In the rat otocyst, staining for connexin26 as well as for connexin30 appeared at the 17th day of gestation. However, at this stage, expression of connexin30 was low and restricted to the neurosensory epithelium. Beginning from the 3rd postnatal day connexin26 and -30 were expressed with highest immunoreaction in the spiral limbus, the neurosensory epithelium, and between the stria vascularis and the spiral ligament. Beginning from postnatal day 12 the staining pattern resembled that of adult animals, with additional strong staining between all fibrocytes of the spiral ligament. Double labeling experiments demonstrated strongest colocalization of both connexins between the stria vascularis and the spiral ligament. These results demonstrate that development of the cochlear gap junction system precedes the functional maturation of the rat inner ear, which takes place between the 2nd and 3rd postnatal week. In the cochlea of a 22-week-old human embryo, connexin26 and connexin30 could be detected in the lateral wall, suggesting that both connexins also play a crucial role in function of the human inner ear.

Animals↗

PubMed1999

Characteristic growth of human choriocarcinoma xenografts in nude mice.

In order to investigate the mechanisms and regulation of trophoblast vessel invasion, we established a model using malignant trophoblast cells grown in nude mice. The human choriocarcinoma cell line Jeg-3 established fast-growing tumours within 2 weeks after subcutaneous injection into nude mice. Interestingly, instead of neoangiogenesis the tumours were characterized by large blood-filled lacunae. Staining for hCG-beta and for mouse panendothelial antigen revealed that the majority of the lacunae were lined by trophoblast cells. The blood supply of the lacunae resulted from invasion of the choriocarcinoma cells into the host vessels at the junctional zone between tumour and mouse tissue. These large blood-filled lacunae led to a much faster expansion of tumours with less necrotic areas compared to tumours of non-trophoblastic origin (Hec-1A and HeLa), which revealed neovascularization. Jeg-3 choriocarcinoma cells eroded host vessels and replaced the endothelial lining in a similar way to trophoblast cells during the establishment of a haemochorial placenta. This model can be useful in investigating the cell biological mechanisms of trophoblast vessel invasion and replacement of the endothelium by trophoblast cells.

Animals↗

PubMed1999

Connexin expression patterns in human trophoblast cells during placental development.

This study focuses on the gap junction expression pattern in trophoblast cells during human placental development in vivo and in vitro. Investigations of cell-cell communication properties within the subpopulations of trophoblast responsible for invasion, placental growth and feto-maternal transport seem of special interest because the intercellular channels are believed to coordinate proliferation and differentiation processes. From all gap junction connexins (Cx) investigated (Cx26, Cx31, Cx32, Cx37, Cx40, Cx43), Cx40 was the only connexin clearly detected within the cytotrophoblast of human placenta, and was restricted to the extravillous trophoblast of cell islands and cell columns. Most intense staining was found in the juxtastromal area correlated to the proliferating extravillous trophoblast cells. Connexin protein expression was missing during trophoblast migration into the decidua but was re-expressed in trophoblast aggregates within the decidua. Cx40 expression decreased with progressing pregnancy and no connexins could be detected in villous or extravillous trophoblast of mature placentae. In parallel, isolated trophoblast cells of first and second trimester placentae revealed Cx40 expression and, in contrast to the situation in vivo, Cx43 was also found. In isolated cells of mature placentae, expression of both Cx40 and Cx43 transcripts was decreased to low levels and Cx40 immunoreactivity was absent. Cx43 protein, however, was still detectable in trophoblast cultures of term placentae. Our studies suggest that Cx40 is the characteristic channel for the proliferating cell population of cell islands and cell columns of first and second trimester placentae and isolated trophoblast and is probably involved in regulation and coordination of the invasive pathway.

Cell Division↗

PubMed1999

Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat.

Successful pregnancy is strictly dependent on the trophoblast-decidual interaction and on an adequate blood supply to the implantation sites. Nitric oxide (NO) has been shown to play an important role during advanced gestation, although its role during early pregnancy is unclear. The aim of the present study in rats was to evaluate whether NO plays a role during the preimplantation [days 1-4 post coitum (p.c.)] and peri-implantation (days 6-8 p.c.) phases of pregnancy. The rats were treated with the non-specific nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and the iNOS inhibitor aminoguanidine in the presence and absence of low-dose antiprogestin, onapristone, and evaluated on days 9 p.c. and 19 p.c., respectively. Before implantation, the treatments alone (L-NAME, aminoguanidine, onapristone) had little effect on pregnancy outcome. Conversely, aminoguanidine plus onapristone treatment completely prevented pregnancy, whereas L-NAME plus onapristone reduced the pregnancy rate to approximately 50%. In addition, both treatments drastically reduced decidualization. Oviductal flushing experiments revealed arrest of embryo development at around the 8-cell stage after aminoguanidine plus onapristone treatment on days 1-4 p.c. Similarly, treatment during the peri-implantation period with L-NAME, aminoguanidine, and onapristone each had only marginal effects on pregnancy. However, a combination of L-NAME and onapristone, and aminoguanidine plus onapristone prevented pregnancy in 71% and 42% of dams, respectively, as determined on day 19 p.c. These treatments also markedly inhibited the decidualization process. This study demonstrates synergistic effects of NOS inhibitors and an antiprogestin in preventing pregnancy. NOS, particularly the cytokine- and progesterone-inducible iNOS, may represent a new target for novel therapeutic agents capable of promoting or inhibiting pregnancy.

Animals↗

PubMed1999

Gap junction connexin genes cx26 and cx43 are differentially regulated by ovarian steroid hormones in rat endometrium.

In rat endometrium, expression of gap junction connexin-26 (cx26) in the epithelium and cx43 in the uterine stroma is suppressed by progesterone before implantation. For further study of connexin gene regulation we analyzed expression of cx26, cx43, and cx32 in the endometrium of ovariectomized rats treated with different ratios of 17beta-estradiol (E2) and progesterone (P). A hormonal ratio of E2 to P that mimics conditions during pregnancy (0.1 microg E2 and 4 mg P) suppressed expression of cx26 and cx43. By changing the ratio to higher E2 levels (1 microg E2), cx26, in contrast to cx43, was not suppressed even by application of a high P concentration (10 mg). Time-course experiments supplying E2 alone led to an early gene response of cx26 within 3 h, whereas induction of cx43 transcripts was not detected until 14 h after E2 treatment. Simultaneous application of the antiestrogen ICI 182780 abolished E2-mediated induction of both connexins. No hormonal regulation of cx32 could be detected. As already shown for cx43 gene induction in the myometrium, E2-mediated induction of cx26 expression in the endometrium also required newly synthesized transcription factors. It can be concluded that only a hormonal ratio resembling conditions during pregnancy is able to suppress the expression of both cx26 and cx43 and that cx26 gene expression is induced earlier by E2 and is likely to be more sensitive to a shift in the E2 to P ratio than cx43.

Animals↗

PubMed1998

Transplacental uptake of glucose is decreased in embryonic lethal connexin26-deficient mice.

Mice that harbor a targeted homozygous defect in the gene coding for the gap junctional protein connexin26 died in utero during the transient phase from early to midgestation. From day 10 post coitum onwards, development of homozygous embryos was retarded, which led to death around day 11 post coitum. Except for growth retardation, no gross morphological alterations were detected between homozygous connexin26-defective embryos and wild-type littermates. At day 9 postcoitum, when chorioallantoic placenta started to function, connexin26 was weakly expressed in the yolk sac epithelium, between syncytiotrophoblasts I and II in the labyrinth region of the placenta, and in the skin of the embryo. At day 10 post coitum, expression of connexin26 in the placenta was much stronger than at the other locations. To analyze involvement of connexin26 in the placental transfer of nutrients, we have measured embryonic uptake of the nonmetabolizable glucose analogue 3-O-[14C]methylglucose, injected into the maternal tail vein. At day 10 post coitum, viable, homozygous connexin26-defective embryos accumulated only approximately 40% of the radioactivity measured in wild-type and heterozygous littermates of the same size. We conclude that the uptake of glucose, and presumably other nutrients as well, from maternal blood into connexin26-deficient mouse embryos was severely impaired and apparently not sufficient to support the rapid organogenesis during midgestation. Our results suggest that connexin26 gap junction channels likely fulfill an essential role in the transfer of maternal nutrients and embryonic waste products between syncytiotrophoblast I and II in the labyrinth layer of the mouse placenta.

3-O-Methylglucose↗

PubMed1998

Regulation of gap junction connexins in the endometrium during early pregnancy.

In mammalian species embryo implantation into uterine tissue is restricted to a limited time period, the receptive phase. For successful implantation appropriate differentiation of the receptive endometrium is under the control of ovarian steroid hormones. In addition, locally acting embryonic signals are needed to modulate the maternal environment before invasion of the trophoblast is permitted. The expression pattern of gap junction channel proteins, connexins (cx), is directly related to this process. In rodents as well as in rabbit and humans the receptive endometrium is characterized by a lack of such cell-to-cell communication channels. In the rat endometrium cx26 is suppressed in the epithelium and cx43 in the stromal compartment by maternal progesterone, a phenomenon that can be observed similarly in human endometrium. Experimental approaches revealed that both connexin genes react very sensitively to progesterone and estrogen treatment. In rat and rabbit connexin expression is induced locally in the endometrium in response to the implanting blastocyst. In both species this induction of connexins can be mimicked by a traumatic stimulus. In conclusion, suppression of connexin expression in the endometrium is a characteristic cell biological indication for receptivity in different species. The limited induction of direct cell-to-cell communication properties, probably due to locally acting blastocyst signals, seems to be a precondition for embryo implantation.

Animals↗

PubMed1998

Expression of the gap-junction connexins 26 and 30 in the rat cochlea.

Gap junction channels which are responsible for direct intercellular communication are composed of connexin proteins. Different connexins are distributed in a tissue-specific manner. Up to now only connexin26 has been identified to be widely expressed in the inner ear. In order to investigate the role of additional gap junction proteins, the expression of connexin30 and 43 was investigated in the rat cochlea. Connexin26 and connexin30 were both expressed in the spiral limbus, the spiral ligament, the stria vascularis and between supporting cells of the organ of Corti. Double-labeling experiments suggest that both connexins are partly colocalized between cells. Weak staining of connexin43 could only be detected in the stria vascularis, the spiral ligament and between organ of Corti supporting cells. The corresponding transcripts for connexin26, 30 and 43 could be detected by Northern blot analysis. The expression of different gap junction channels in the cochlea suggests functional diversity. Gap junctions in the inner ear may control ion concentrations of cochlear fluids or act as conduits through which glucose and other metabolites diffuse.

Animals↗

PubMed1997

Expression of connexin31 and connexin43 genes in early rat embryos.

Gap junctions have been reported to play a pivotal role in coordinating embryonic development. Here we report the temporal and spatial pattern of connexin31 that has been found to be coexpressed with connexin43 in preimplantation rat embryos. Connexin31 and connexin43 transcripts are abundant in the zygote and degraded in the two- and four-cell stage to low levels for connexin31 and to undetectable ones for connexin43. The uncompacted eight-cell stage lacks the transcripts of both connexins. Reexpression of connexin43 and connexin31 mRNA is found from the compacted eight-cell stage onward. The connexin31 antigen, however, is already detected intracellularly at the uncompacted eight-cell stage. At the blastocyst stage, both connexins are coexpressed in the trophectoderm as well as in the inner cell mass. After implantation, compartmentalization of both connexins is observed. Connexin31 is now expressed exclusively by the cells of the ectoplacental cone and extraembryonic ectoderm, whereas connexin43 is restricted to the cells of the embryo proper. This compartmentalization in connexin expression between the derivatives of the inner cell mass and the trophectoderm may maintain the different developmental programs. THus, connexin31 seems not to be related to the first step in trophoblast lineage development and could serve as a compensatory channel during preimplantation development.

Animals↗

PubMed1997

Aberrant expression pattern of gap junction connexins in endometriotic tissues.

The expression of gap junction connexins (Cx) in the female reproductive tract of rodents and in the human endometrium is highly regulated by steroid hormones. Here we have investigated the distribution and regulation properties of Cx43, Cx26 and Cx32 in the human ectopic endometrium of 41 patients, using immunohistochemistry. The biopsies were obtained during the early or late follicular phase (26 cases), during the corpus luteum phase (five cases) and after a 6 month treatment with a gonadotrophin-releasing hormone (GnRH) agonist (three cases) or progestin (seven cases). Aberrant expression of Cx43 was found in the epithelium of nearly all endometriotic glands whereas Cx26, typical for human uterine epithelium cells, was only detected in 18 cases; in 17 it was co-expressed with Cx43. The stromal compartment of the tissues did not express any connexins investigated. Staining for Cx32 was absent in all endometriotic tissues. Strong expression of Cx43 was correlated with a high serum value of 17 beta-oestradiol, whereas a strong expression of Cx26 was found with high values of progesterone mainly in patients after progestin treatment. The epithelium of endometriotic implants collected after GnRH agonist treatment expressed Cx26 and Cx43 only moderately. The patterns described demonstrate an aberrant connexin expression and a different hormonal regulation pattern in endometriotic tissues compared to the normal cyclic uterine endometrium, thus indicating a high dedifferentiation from the normal situation. However, endometriosis still remains a hormonally-dependent benign disease, and hence, can be treated hormonally.

Adult↗

PubMed1996

Regulation of connexin31 gene expression upon retinoic acid treatment in rat choriocarcinoma cells.

The controlled invasiveness of the trophoblast is based on the balance between invasive properties at implantation and the differentiation program of the developing placenta. During placental development in rats a switch of connexin gene expression has been observed in parallel to the switch from the invasive to the differentiated phenotype of trophoblast cells. To investigate the role of connexin expression for trophoblast invasion, proliferation, and differentiation, we studied one rat trophoblast (HRP-1) and one rat choriocarcinoma cell line (Rcho-1). The choriocarcinoma cells were characterized by expression of cx31 and a lack of E-cadherin, corresponding to the invasive trophoblast in vivo, whereas HRP-1 cells expressed cx43, normally found in the spongiotrophoblast and in late giant cells, and E-cadherin. Upon retinoic acid treatment, Rcho-1 cells irreversibly lost cx31 expression, accompanied by a loss of functional coupling. No changes in regard to connexin expression and cell-cell communication could be observed in HRP-1 cells. In addition, treatment of Rcho-1 cells with retinoic acid for 7 days upregulated expression of cx43 transcript, but no protein could be found. Proliferation was clearly reduced and the mean volume of cells doubled from Day 4 to Day 7 of retinoic acid treatment in Rcho-1 cells, while both parameters were not affected in HRP-1 cells. Both cell lines showed a similar invasion rate using a Matrigel invasion assay, and invasion was equally suppressed upon retinoic acid treatment. Thus the different connexin expression appears more likely to play a role in regulating proliferation and differentiation along the multilineage pathway than invasiveness of rat trophoblast cells.

Animals↗

PubMed1996

Wild type neu transgene counteracts mutant homologue in malignant transformation of rat Schwann cells.

Mutational activation of the neu (erbB-2) receptor protein tyrosine kinase gene appears to be the triggering event in the process of oncogenesis induced by N-ethyl-N-nitrosourea (EtNU) in immature Schwann cells of the rat peripheral nervous system. Subsequent loss of the wild-type neu allele may represent a critical secondary step towards malignancy. Developmentally-regulated expression of a wild-type rat neu transgene (neu cDNA under the control of the rat Po promoter) in the Schwann cells of transgenic BDIX and Sprague-Dawley rats exposed to EtNU on postnatal day 1 results in a lower incidence of early atypical proliferates in the trigeminal nerve. Furthermore, re-introduction of the wild-type neu gene into homozygous neu mutant schwannoma cells counteracts the expression of the tumorigenic phenotype. The suppressive action of the wild-type gene over its mutationally activated oncogenic homologue underlines the critical function of the neu gene in the control of differentiation in the Schwann cell lineage, and provides evidence for the responsiveness of cellular phenotypes towards quantitative shifts in the dosage of wild-type vs mutant signal transducing molecules.

Alleles↗