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PubMed1995

Transitional differentiation patterns of principal and intercalated cells during renal collecting duct development.

The developing renal collecting duct epithelium of neonatal rabbits exhibits 3 different zones. The ampullary tip epithelium acts as an embryonic inducer and is responsible for the generation of all of the nephron anlagen. It pilots the whole microarchitecture of the kidney. In the ampullary neck epithelium multiple cell divisions cause the elongation of the embryonic collecting duct so that the organ can grow. Finally, the cells in the ampullar shaft transdifferentiate into the functional collecting duct epithelium (CD) consisting of Principal (P) and various kinds of Intercalated (IC) cells. It is unknown by which morphogenic mechanisms the ampullar cells develop into the heterogeneously composed collecting duct epithelium. Using both morphological and immunohistochemical methods, we investigated the transdifferentiation patterns leading from the ampullar epithelium to the P and IC cells in the neonatal kidney. An electron microscope analysis of the cortico-medullary course of the developing collecting duct revealed that conspicuous morphological alterations start in the neck of the ampulla. The lumen of the neck region is narrowed to a slit. While most of the cells in the ampullar tip exhibit few, short microvilli, the neck cells bear numerous, extremely long microvilli at their apical cell poles. All of the neck cells exhibit the same cytoplasmic staining pattern and the same number of mitochondria. Farther down in the shaft, clearly recognizable P and IC cells are found. Thus, differentiation into P and IC cells starts with a transitional precursor cell type in the ampullar neck. Perfusion culture experiments with the embryonic collecting duct epithelium made it possible to generate transitional and differentiated cell types for the first time under in vitro conditions. The cultured epithelial cells showed characteristics common to both P and IC cells. Immunohistochemical findings revealed that morphological differentiation starts before the functional properties of P and IC cells can be detected.

Animals↗
PubMed1997

[Elucidation of the mechanism of retinal degeneration and regeneration and the prospects for its clinical application].

In order to obtain the basic knowledge necessary to develop therapeutical intervention for blindness due to the damaged retina and optic nerve, the mechanism of retinal degeneration and regeneration in an amphibian model, Cynops pyrrhogaster, was studied. In the retinal degenerative process following enucleation and reimplantation of the eye ball, evidence was found for active cell death of neural retinal cells. As the degeneration proceeded, Musashi, an ribonucleic acid (RNA)-binding protein, started its expression in the daughter cells of proliferating retinal pigment epithelium (RPE) cells, messenger RNA (mRNA) expression of proneural genes with basic helix-loop-helix motif was then detected in the newly developing retina. These results suggest that transdifferentiation of RPE cells to neural retina involves at least partial cascade, if not entirely, of neural induction from uncommitted ectodermal tissue. Search for genes that are required for transdifferentiation of RPE cells to neural retinal cells, in addition to those mentioned above, will provide the basic knowledge for successful retinal transplantation and retinal regeneration in higher vertebrates.

Amphibians↗
PubMed2025

Synostosis of joints caused by mutant FBN2 is linked to the abnormalities and misdifferentiation of articular surface cells.

PURPOSE: FBN2, a high-confidence effector gene for osteoarthritis (OA), was investigated for its potential role in synostosis of joints (SJ) because several OA-related genes are known to cause SJ. METHODS: We analyzed variants in OA-related genes using exome sequencing data from Chinese-Han participants with radioulnar synostosis (RUS). Variants were classified following American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Fbn2 knockout mice were generated via CRISPR/Cas9 and evaluated through radiological and histopathological analyses at multiple developmental stages, with complementary cellular and molecular studies. RESULTS: We identified 15 rare, damaging FBN2 variants in unrelated RUS families, including 7 likely pathogenic variants (4 null variants). Fbn2 knockout mice (both homozygous and heterozygous) exhibited SJ phenotypes. Unlike previously reported SJ mechanisms involving failed interzone formation, Fbn2-related SJ occurred after normal interzone formation. Mutant mice showed significant alterations in extracellular matrix composition and volume within articular surface cells. We proposed that these extracellular matrix changes mediated the transdifferentiation of articular surface cells into osteoblasts, which ultimately developed into bones over time. CONCLUSION: We identified FBN2 pathogenic variants that caused SJ in humans and mice. SJ caused by mutant FBN2 is linked to the abnormalities and misdifferentiation of articular surface cells.

Fibrillin-2↗
PubMed2004

Gastric PDX-1 expression in pancreatic metaplasia and endocrine cell hyperplasia in atrophic corpus gastritis.

The homeodomain transcription factor PDX-1 plays a key role in endocrine and exocrine differentiation processes of the pancreas. PDX-1 is also essential for differentiation of endocrine cells in the gastric antrum. The role of PDX-1 in the pathogenesis of endocrine cell hyperplasia and pancreatic metaplasia in corpus and fundus gastritis has not been evaluated. By immunohistochemistry and double-immunofluorescence, we investigated the expression of PDX-1 in 10 tissue specimens with normal human gastric mucosa, nonatrophic and atrophic gastritis and in pancreatic metaplasia, respectively. In normal corpus mucosa and in nonatrophic corpus gastritis, PDX-1 was mainly absent. In pancreatic metaplasia, PDX-1 was found in metaplastic cells and in adjacent gastric glands. In contrast to normal gastric corpus mucosa, PDX-1 could be strongly detected in the cytoplasm of the parietal cells surrounding metaplastic areas. Furthermore, PDX-1 expression was found in hyperplastic endocrine cells and in the surrounding gastric glands in chronic atrophic gastritis. Hyperplastic endocrine cells coexpressed the beta-subunit of the gastric H,K-ATPase. We conclude that PDX-1 represents a candidate switch factor for glandular exocrine and endocrine transdifferentiation in chronic gastritis and that an impaired parietal cell differentiation might play a key role in disturbed gastric morphogenic processes.

Adult↗
PubMed1997

Impression cytology study of epithelial phenotype of ocular surface reconstructed by preserved human amniotic membrane.

OBJECTIVE: To determine the epithelial phenotype of the ocular surface reconstructed by preserved human amniotic membrane. METHODS: Impression cytology was performed in 6 patients who received a large patch of amniotic membrane for conjunctival surface reconstruction during removal of acquired melanosis, conjunctival intraepithelial neoplasia, or bilateral inferior conjunctival chalasis, or for corneal surface reconstruction during removal of pannus associated with limbal deficiency caused by aniridia, toxic epidermal necrolysis, or chemical burn. RESULTS: The nongoblet epithelial cells covering the amniotic membrane were uniformly smaller and the cell density was almost twice that of age- and sex-matched normal control eyes at the corresponding site, and the goblet cell density was almost 10 times that of the control (both P < .05; Student paired t test) (N = 7 eyes). Furthermore, the conjunctival epithelial phenotype with goblet cells was found on corneal surfaces of all 3 patients with limbal deficiency. CONCLUSIONS: The success of conjunctival surface reconstruction correlated well with recovery of the conjunctival epithelial phenotype. The lack of corneal epithelial phenotype even on an avascular corneal stroma supports the concept that conjunctival transdifferentiation does not occur in vivo, and indicates that additional limbal stem cell transplantation is needed for effective corneal surface reconstruction in patients with limbal deficiency.

Adult↗
PubMed1997

Development of nicotinic receptor clusters and innervation accompanying the change in muscle phenotype in the mouse esophagus.

During development, the external muscle of the mouse esophagus undergoes a transdifferentiation from smooth to striated muscle (Patapoutian et al. [1995] Science 270:1818-1821). We now report on the development of the innervation accompanying the change in phenotype of the external muscle of the mouse esophagus. The phenotype of the muscle was monitored by using light and electron microscopy. Nicotinic acetylcholine receptors were localised by using a fluorescence conjugate of alpha-bungarotoxin, and neural elements were localised by using antisera to synaptophysin (a synaptic vesicle protein that was used to label all nerve terminals), the vesicular acetylcholine transporter (VAChT), calcitonin gene-related peptide (CGRP), nitric oxide synthase (NOS), and vasoactive intestinal peptide (VIP). CGRP and VAChT were co-localised in the terminals of vagal motoneurons that innervate the external muscle, and NOS and VIP were co-localised in intrinsic (enteric) neurons, which provide some terminals that are associated with motor endplates. Cells exhibiting striations were first observed in the outer layers of the most rostral regions of the esophagus of embryonic day 15 (E15) mice. Clusters of nicotinic acetylcholine receptors were also first observed at the rostral end of the esophagus of E15 mice, and developed in a rostrocaudal progression that coincided with the appearance of striations within the muscle cells. Synaptophysin-, VAChT- and NOS-immunoreactive nerve terminals were present within the external muscle prior to the formation of receptor clusters, and their appearance did not follow any apparent rostrocaudal sequence. Surprisingly, not all of the receptor clusters at E15 had synaptophysin- and VAChT-immunoreactive nerve terminals closely associated with them. However, from E18 on, almost all of the clusters had synaptophysin-immunoreactive nerve terminals in close association. At late embryonic and early postnatal stages, there was a rostrocaudal gradient in the proportion of receptor clusters having VAChT-immunoreactive nerve terminals associated with them. Nerve terminals associated with nicotinic receptor clusters did not show detectable CGRP-immunoreactivity until one to two weeks after the appearance of synaptophysin- and VAChT-immunoreactivity. The NOS-immunoreactive neurons did not show detectable VIP-immunoreactivity until three days after NOS could be detected. These results show that the appearance of clusters of nicotinic receptors in the external muscle of the esophagus coincides with the expression of a striated muscle phenotype, but not with the presence of ingrowing nerve terminals. However, many of the receptor clusters that were observed first were apparently uninnervated.

Acetylcholine↗
PubMed1998

Ultrastructure of the olfactory organ in the clawed frog, Xenopus laevis, during larval development and metamorphosis.

Development of the olfactory epithelia of the African clawed frog, Xenopus laevis, was studied by scanning and transmission electron microscopy. Stages examined ranged from hatching through the end of metamorphosis. The larval olfactory organ consists of two chambers, the principal cavity and the vomeronasal organ (VNO). A third sensory chamber, the middle cavity, arises during metamorphosis. In larvae, the principal cavity is exposed to water-borne odorants, but after metamorphosis it is exposed to airborne odorants. The middle cavity and the VNO are always exposed to waterborne odorants. Electron microscopy reveals that in larvae, principal cavity receptor cells are of two types, ciliated and microvillar. Principal cavity supporting cells are also of two types, ciliated and secretory (with small, electron-lucent granules). After metamorphosis, the principal cavity contains only ciliated receptor cells and secretory supporting cells, and the cilia on the receptor cells are longer than in larvae. Supporting cell secretory granules are now large and electron-dense. In contrast, the middle cavity epithelium contains the same cell types seen in the larval principal cavity. The VNO has microvillar receptor cells and ciliated supporting cells throughout life. The cellular process by which the principal cavity epithelium changes during metamorphosis is not entirely clear. Morphological evidence from this study suggests that both microvillar and ciliated receptor cells die, to be replaced by newly generated cells. In addition, ciliated supporting cells also appear to die, whereas there is evidence that secretory supporting cells transdifferentiate into the adult type. In summary, significant developmental additions and neural plasticity are involved in remodeling the olfactory epithelium in Xenopus at metamorphosis.

Animals↗
PubMed1998

Cellular terrain surrounding sympathetic nerve pathways in the rat orbit: comparisons of orbital connective tissue and smooth muscle cell phenotypes.

Sympathetic axons are abundant within some orbital tissues but are absent from others. This study investigated cellular phenotypes of tissues containing sympathetic nerves en passage and compared these with phenotypes in regions devoid of sympathetic nerves and with smooth muscle targets. Two primary orbital smooth muscle targets, the tarsal muscle and orbital muscle, contained many synaptophysin-immunoreactive nerves. Target cells had ultrastructural features typical of smooth muscle and were immunoreactive for alpha-smooth muscle actin, smooth muscle myosin heavy chain, desmin, vinculin, and laminin, but not non-muscle myosin, vimentin, fibronectin, or type IV collagen; nerve growth factor (NGF) mRNA was detected by reverse transcription-polymerase chain reaction. Periorbital sheath devoid of sympathetic nerves contained elongated fibroblasts that were immunoreactive for vimentin, non-muscle myosin, and fibronectin, but not for alpha-smooth muscle actin, smooth muscle myosin heavy chain, vinculin, desmin, laminin, or type IV collagen, and did not express NGF mRNA. Regions of periorbital sheath containing sympathetic nerves had few synaptophysin-immunoreactive varicosities. Cells in this region contained myofilaments, ribosomes, and rough endoplasmic reticulum and were larger than tarsal muscle cells. They expressed NGF mRNA and showed a unique immunophenotype, reacting for vimentin, alpha-smooth muscle actin and myosin heavy chain, desmin, vinculin, laminin, and type IV collagen. This phenotype reflects both fibroblast and smooth muscle features similar to myofibroblasts or transdifferentiated smooth muscle described in other tissues. The spatial association between these cells and sympathetic nerves suggests that they may be involved in axon guidance or maintenance.

Animals↗
PubMed1998

Cytokeratins and cell differentiation in the pancreas.

Keratins, or cytokeratins, represent a family of more than 20 different polypeptides which are important markers of epithelial cell differentiation. This review deals with the use of keratin immunohistochemistry in the study of pancreatic cell differentiation. Exocrine acinar cells and endocrine islet cells are well-differentiated cells which express the keratin combination 8 and 18, whereas the less-differentiated cells of the ductal tree are characterized by the additional expression of keratin 7, keratin 19, and, in the rat, keratin 20. Keratin expression is stable and can be used for cell identification after isolation and culture, and in clinical or experimental injury. The intercalated ductal cells and centroacinar cells are inconspicuous unless specific immunohistochemical markers, such as keratins, are used. In conditions where there is morphogenetic differentiation such as in fetal life, or where transdifferentiation is occurring, keratins have been used to trace the origin and fate of pancreatic cells.

Biomarkers↗
PubMed1996

Ovotestis variability in young and adult females of the mole Talpa occidentalis (insectivora, mammalia).

The age-related evolution and ontogenic origin of the ovotestes in fertile females of the Spanish mole (Talpa occidentalis) were studied. Volume of the ovotestis and its ovarian and testicular components, size of the epididymis and testicular cords, number of ovarian follicles and testicular cords, uterus weight, and age index were analyzed statistically in a large sample of young and adult individuals of this species. Comparison of means and linear correlation analyses were done. Most variables were shown to be age dependent, with a period of rapid change during puberty. In adult animals, volume of the ovarian portion and uterus weight followed a seasonal cycle of sexual activity. Interindividual variability was evident in most of the variables investigated except for the number of testicular cords per ovotestis, which remained unchanged throughout the animal's life and hence was not inversely correlated with the number of ovarian follicles. This finding ruled out an ovary-testis transdifferentiation hypothesis for the ontogenic origin of the testicular tissue in the ovotestes of female moles. An alternative hypothesis based in the absence of oocytes in a portion of the undifferentiated fetal gonad is proposed in accordance with a new general model for mammalian sex determination.

Animals↗
PubMed2000

Hepatoid carcinoma of the pancreas.

BACKGROUND: The majority of primary extrahepatic neoplasms exhibiting features of hepatocellular carcinoma in terms of morphology, immunohistochemistry, and behavior have been described in the stomach. To the authors' knowledge only a few cases have involved other organ sites. They frequently are associated with other histologic type tumors such as adenocarcinoma, and portend an aggressive behavior. METHODS: Two examples of hepatoid carcinoma arising from the pancreas are reported in the current study. RESULTS: One case was a malignant islet cell tumor with a full-blown clinical syndrome of glucagon overproduction, histologic evidence of hepatocytic differentiation, bile production, and alpha-fetoprotein (AFP) positivity. The second tumor was a ductal carcinoma showing periodic acid-Schiff positive and diastase-resistant hyaline globules, AFP production, and ultrastructural resemblance to hepatocytic cells. CONCLUSIONS: The rare observation of cellular phenotypic transformation that corresponds with the process of hepatocytic transdifferentiation of pancreatic cells demonstrated in animal models and the common embryologic foregut derivation of the pancreas and liver also may explain the phenomenon of pancreatic hepatoid carcinoma.

Adult↗
PubMed1996

Glucocorticoids, tumor necrosis factor-alpha, and epidermal growth factor regulation of pulmonary morphogenesis: a multivariate in vitro analysis of their related actions.

The mouse lung commences development on embryonic day 11 as an epithelial evagination from the posterior pharyngeal wall into undifferentiated mesenchyme, this epithelium bifurcating to form the lung primordium. Branching morphogenesis, as well as terminal differentiation, requires epithelial-mesenchymal interactions utilizing precise regulatory controls. Not surprisingly, specific hormones and growth factors appear to play a key role in this regulation. We report here a series of experiments designed to investigate morphodifferentiation (epithelial branching number, generation number, and fractal dimension) and histodifferentiation (cell morphology and SP-A immunolocalization), as they relate to glucocorticoid (CORT)-regulation of growth factor function and expression (Northern analysis). These experiments were conducted in embryonic lung primordia (E11.5-E12) cultured under defined conditions in the presence of single or combined CORT, TNF-alpha, and EGF supplementation. EGF supplementation enhances branching morphogenesis, but not immunodetectable SP-A expression, in embryonic lung primordia cultured for 4 or 7 days. TNF-alpha supplementation also enhances branching morphogenesis on days 4 or 7 in vitro; on day 7, SP-A expression is also enhanced. By contrast, the introduction of exogenous CORT to embryonic explants cultured 4 or 7 days markedly alters morphodifferentiation and histodifferentiation. Early on it would appear to enhance morphodifferentiation by changing the process of branching, while contemporaneously initiating precocious SP-A expression; later on, it alters morphogenesis by continued terminal differentiation of normal lung epithelium and a singular transdifferentiation of lung mesenchyme into an epithelioid morphotype expressing SP-A. This is correlated with a CORT-induced, highly significant, down-regulation of TGF-beta 2 and TGF-beta 3 transcripts. Explants supplemented with CORT + TNF-alpha or CORT + EGF.demonstrate a microanatomy and SP-A expression pattern identical to that seen with CORT supplementation alone. EGF inhibits the accelerated lung maturation normally seen in the presence of exogenous TNF-alpha alone, suggesting a relationship between these two seemingly disparate regulatory pathways.

Animals↗
PubMed1997

Characterization of the fate of midline epithelial cells during the fusion of mandibular prominences in vivo.

The fusion of the mandibular prominences along the midline is achieved with the absence of medial epithelial cells at the fusion site. Failure of fusion of the mandibular prominences results in median cleft of the lower lip and mandible. Cellular and molecular events controlling mandibular fusion were examined during the fusion process in mouse embryogenesis. Cell lineage analyses at the fusion site revealed that epithelial cells migrated to the surface and oral epithelia. DiI-labeled epithelial cells were not observed within the mandibular mesenchyme at any state of fusion. Examination of the midline region did not reveal cells with ultrastructural changes characteristic of apoptotic cell death. An increase in lysosomal enzymes in the midline epithelial cells, which would be correlated with programmed cell death, was not observed. Mice lacking TGF-beta 3 did not have cleft mandible, but had clefting of the secondary palate as a feature of null mutation phenotype. We interpret our comparisons between wild type and homozygous TGF-beta 3 (-/-) mice to suggest that different developmental processes control palatal vs. mandibular fusion. We hypothesize that medical epithelial cells at the fusion site of mandibular prominences migrate to the surface epithelium during the fusion process and neither transdifferentiate into mesenchyme nor express apoptosis.

Animals↗
PubMed2000

Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro.

Vascular proliferative disorders are characterized by migration and proliferation of vascular smooth muscle cells (SMCs), loss of expression of SMC phenotype, and enhanced extracellular matrix synthesis (e.g., type I collagen). We report here that bone morphogenetic protein-7 (BMP-7), a member of the transforming growth factor-beta (TGF-beta) superfamily, is capable of inhibiting both serum-stimulated and growth factor-induced (platelet-derived growth factor [PDGF-BB] and TGF-beta1) cell growth as measured by (3)H-thymidine uptake into DNA synthesis and cell number in primary human aortic smooth muscle (HASM) cell cultures. Concomitantly, addition of BMP-7 stimulates the expression of SMC-specific markers, namely alpha-actin and heavy chain myosin as examined by RT-PCR and Northern blot analyses. The collagen type III/I ratio that becomes lower with the transdifferentiation of SMCs into myofibroblasts is also maintained in BMP-7-treated cultures as compared to untreated controls. Studies on the mechanism of action indicate that BMP-7 treatment inhibits cyclin-dependent kinase 2 (cdk-2) that was stimulated during PDGF-BB-induced proliferation of SMCs and upregulates the expression of the inhibitory Smad, Smad6, which was shown to inhibit TGF-beta superfamily signaling. These results collectively suggest that BMP-7 maintains the expression of vascular SMC phenotype and may prevent vascular proliferative disorders, thus potentially acting as a palliative after damage to the vascular integrity.

Actins↗
PubMed1997

Na+ and Ca2+ channel expression in cultured newt retinal pigment epithelial cells: comparison with neuronal types of ion channels.

We cultured retinal pigment epithelial (RPE) cells dissociated from adult newt eye and analyzed their voltage-gated ion channels during culture using whole-cell patch-clamp techniques. The results were compared with those of retinal neurons under identical experimental conditions. After 6-9 days in culture (early stage), > 60% of RPE cells developed voltage-gated Na+ and Ca2+ channels that were not observed in freshly dissociated RPE cells. The number of cells expressing Na+ channels and Na+ current density were high after 12-15 days in culture (intermediate stage), while the number of Ca2+ channel-expressing cells and Ca2+ current density were high after 20-30 days in culture (late stage). The activation voltage of the Na+ current in the RPE cells was similar to that in neurons. The voltage dependence of Na+ current inactivation was somewhat different between two cell types. The steepness of the inactivation curve tended to be less in cultured RPE cells than in neurons, and the half-inactivation voltage was about-54 mV for the RPE cells and -45 mV for neurons. The Ca2+ current expressed in cultured RPE cells was too small to detect without replacement of external Ca2+ with Ba2+. The Ba2+ current, like Ca2+ current in neurons, was enhanced by Bay-K 8644 and blocked by nicardipine. These results suggest that the RPE cells, like neurons, expressed L-type Ca2+ channels in culture. The possibility that the development of both Na2+ and Ca2+ channels in cultured RPE cells is a manifestation of the transdifferentiation of RPE cells into neurons is discussed.

Animals↗
PubMed1999

Use of representational difference analysis to study the effect of TGFB on the expression profile of a pancreatic cancer cell line.

It has been shown that TGFBs, their receptors, or downstream targets show genetic alterations in pancreatic cancer. This study was designed to identify transcriptional alterations induced by prolonged treatment of pancreatic cancer cell lines with TGFB. The TGFB-responsive PANC-1 cell line was treated with 10-ng/ml TGFB1 for 24 hr. cDNA representational difference analysis was used to generate subtracted hybridization probes enriched for TGFB regulated genes. These probes were hybridized on gridded arrays of cDNA clones containing genes differentially expressed in pancreatic cancer. Twenty-seven distinct cDNA clones were shown to be TGFB target genes. Eleven genes were upregulated by TGFB and were associated with extracellular matrix composition and formation, including genes usually transcribed by cells of mesenchymal origin only. Transcript levels of 16 genes were downregulated by TGFB and could mainly be classified into markers of epithelial differentiation and genes involved in the transcriptional and translational machinery. In conclusion, a 24-hr treatment of PANC-1 cells with TGFB induced a loss of epithelial and a gain of mesenchymal markers. As in other tumors, this epithelial-mesenchymal transdifferentiation may be of general importance during pancreatic carcinogenesis, and may participate, e.g., in the development of the desmoplastic reaction or the acquisition of an invasive phenotype of pancreatic tumor cells. This study demonstrates the usefulness of cDNA RDA and gridded clone libraries to study the effect of signaling cascades on the expression profile of tumor cells. Similar approaches may be helpful in the context of the genome project for the characterization of novel genes. Genes Chromosomes Cancer 26:70-79, 1999.

Cell Division↗
PubMed1998

Interactions between SRY and SOX genes in mammalian sex determination.

The SRY gene on the mammalian Y chromosome undoubtedly acts to determine testis, but it is still quite unclear how. It was originally supposed that SRY acts directly to activate other genes in the testis-determining pathway. This paper presents an alternative hypothesis that SRY functions indirectly, by interacting with related genes SOX3 (from which SRY evolved) and SOX9 (which appears to be intimately involved in vertebrate gonad differentiation). Specifically, I propose that in females SOX3 inhibits SOX9 function, but in males, SRY inhibits SOX3 and permits SOX9 to enact its testis-determining role. This hypothesis makes testable predictions of the phenotypes of XX and XY individuals with deficiencies or overproduction of any of the three genes, and is able to account for the difficult cases of XX(SRY-) males and transdifferentiation in the absence of SRY. The hypothesis also suggests a way that the dominant SRY sex-determining system of present-day mammals may have evolved from an ancient system relying on SOX3 dosage.

Animals↗
PubMed1990

Papillary cystic tumor of the liver. A case report with ultrastructural observation.

A case of primary tumor of the liver with pathologic features strikingly similar to those of the papillary cystic tumor of the pancreas in a 41-year-old woman is presented. Two large, well-demarcated, solid and cystic tumors with extensive hemorrhage and necrosis were located in the right and left lobes, measuring 30 x 27 x 7.5 cm and 5.5 x 4.0 x 2.5 cm, respectively. Microscopically, both tumor masses showed two basic patterns of cellular arrangement. One was a papillary pattern with fairly prominent fibrovascular stalks covered with one to three cell layers of tall to cuboidal cells. The other pattern was that of solid growth with microcystic degeneration. Ultrastructurally, the tumor cells were polyhedral and their oval shaped nuclei were occasionally indented. The cytoplasmic organelles varied in amount, and immature cell junctions and intercellular spaces were rarely present. A few cells contained zymogen-like secretory granules and annulate lamellae. The pancreas was free of tumor. To our knowledge, this tumor is a unique clinicopathologic entity of hepatic origin, and its similarity to the pancreatic papillary cystic tumor in clinical, gross, microscopic, and ultrastructural features together with their closely related organogenesis, suggests that this tumor derives from pluripotential cells transdifferentiating toward the pancreatic acinar cells and ductular cells, with the latter being indistinguishable from intrahepatic small bile ductular epithelial cells.

Adult↗