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At least 19 recordsLinked to original sources
PubMed2000

Repression of the putative tumor suppressor gene Bard1 or expression of Notch4(int-3) oncogene subvert the morphogenetic properties of mammary epithelial cells.

We have investigated whether repression of the putative tumor suppressor gene BARD1 or expression of the Notch4(int-3) oncogene in non-tumorigenic mammary epithelial cells affects their in vitro morphogenetic properties. Bard1 (Brca1-associated ring domain) is a protein interacting with Brca1 and thought to be involved in Brca1-mediated tumor suppression. To investigate the potential role of Bard1 in mammary gland development, we repressed its expression in TAC-2 cells, a murine mammary epithelial cell line which, when grown in three-dimensional collagen gels, forms branching ducts in response to hepatocyte growth factor (HGF) and alveolar-like cysts in response to hydrocortisone. Whereas Bard1 repression did not markedly modify the tubulogenic response of TAC-2 cells to HGF, it dramatically altered cyst development, resulting in the formation of compact cell aggregates devoid of central lumen. In addition, when grown to post-confluence in two-dimensional cultures, Bard1-suppressed TAC-2 cells overcame contact-inhibition of cell proliferation and formed multiple cell layers. The Notch4(int-3) oncogene, which codes for a constitutively activated form of the Notch4 receptor, has been reported to induce undifferentiated carcinomas when expressed in the mammary gland. The potential effect of activated Notch4 on mammary gland morphogenesis was investigated by retroviral expression of the oncogene in TAC-2 cells. Notch4(int-3) expression was found to significantly reduce HGF-induced tubulogenesis and to markedly inhibit hydrocortisone-induced cyst formation. In addition, Notch4(int-3) expressing TAC-2 cells formed multilayers in post-confluent cultures and exhibited an invasive behavior when grown on the surface of collagen gels. Taken together, these results indicate that both repression of Bard1 and expression of Notch4(int-3) disrupt cyst morphogenesis and induce an invasive phenotype in TAC-2 mammary epithelial cells.

Breast↗
PubMed1996

Understanding mammary gland development through the imbalanced expression of growth regulators.

Functional differentiation of mammary tissue progresses in distinct phases spanning puberty and pregnancy. Here we have analyzed and compared the effects of transforming growth factor beta 1 (TGF beta 1), TGF alpha, and whey acidic protein (WAP), the Notch-related cell fate protein Int3, and p53 and pRb on mammary development. We chose transgene expression from the WAP gene promoter which is only active in mammary alveolar cells. The imbalanced expression of these molecules specifically altered development and differentiation of the gland. While TGF alpha did not disturb alveolar outgrowth, little or no alveolar structures developed in the presence of Int3. TGF beta 1, WAP, and the expression of SV40 T-antigen-which inactivates p53 and PRb-reduced overall alveolar development. The expression of individual milk protein genes was affected differentially by the transgenes. A WAP-lacZ transgene served as an additional indicator of terminal differentiation of alveolar cells, Homogeneous expression of lacZ was seen in mice transgenic for lacZ, or for TGF alpha and lacZ. In contrast, only a few differentiated cells were observed in the presence of TGF beta 1 and Tag. Thus, the expression of growth regulators in the same defined subset of mammary cells results in distinct developmental changes and a specific pattern of alveolar differentiation.

Animals↗
PubMed2001

Distinct and regulated expression of Notch receptors in hematopoietic lineages and during myeloid differentiation.

Hematopoietic development is a delicate balance of cell fate decisions in multipotent cells between self-renewal and differentiation. In multiple developmental systems, the Notch receptors are important factors regulating these processes. Hematopoietic progenitor cells have been shown to express Notch1, and studies with an activated intracellular form has revealed a functional role. To assess the function of other Notch members in hematopoiesis, we investigated the expression pattern of Notch1, Notch2, and Notch3 in hematopoietic lineages at the level of RNA and protein. We demonstrate that Notch1 and Notch2 are expressed in multiple lineages, and that Notch1 in particular appears to be regulated during myeloid differentiation. Notch1 was up-regulated and expressed at high levels in adherent macrophages. Mast cells expressed only low levels of Notch1 mRNA whereas Notch2 mRNA was highly expressed. In addition we could detect Notch3 mRNA and protein in cell lines representing mast cell progenitors. These expression patterns imply that the different Notch genes may have very distinct functions during hematopoiesis, and that Notch3 could be a specific regulator of mast cell development. The finding that Notch1 was up-regulated in the adherent cells developing from a multipotent progenitor cell line suggests that this protein may posses dual functions in hematopoiesis, i.e. at the stage of cell fate decision, and at the maturation stage of monocytes when adhesion to the specific microenvironment is accomplished.

Animals↗
PubMed2003

Olfactory ensheathing cells of the lamina propria in vivo and in vitro.

Olfactory ensheathing cells (OECs) continuously support the regeneration of olfactory receptor neurons (ORNs). In addition, OECs promote regeneration of neurons within the CNS in a number of transplantation paradigms, but details of exactly how they support regeneration remain elusive. The majority of studies using OECs to promote regeneration have thus far focused on understanding the cell biology of OECs purified from the olfactory bulb (OB). Here we show that a population of OECs similar to those obtained from the OB is present in the lamina propria (LP) beneath the olfactory epithelium (OE). These OECs are the first glial cells encountered by the axons of developing ORNs as they exit the OE and display distinct and variable expression of p75, S100beta, GFAP, and O4, characteristic markers of bulb OECs. Once purified in vitro, they display Schwann cell-like and astrocyte-like properties and expand rapidly. In addition to resembling OB-OECs, LP-OECs also express a unique combination of developmentally important proteins-CD 44, beta1 integrin, P200, Notch 3, NG2, VEGF, and PACAP and CREB binding protein (CBP/p300)-not previously reported in OB-OECs. These data suggest that LP-OECs, like OB-OECs, are a developmentally distinct class of glia that are capable of both immature and mature function, depending on environmental stimuli, within the adult nervous system.

Animals↗
PubMedDate not supplied

Expression of Notch pathway components in spermatogonia and Sertoli cells of neonatal mice.

Members of the Notch gene family have been shown to play an important role in the control of cell fate in many developmental systems. We hypothesized that the fate of the male germ line stem cells may also be mediated through the Notch signaling pathway. We therefore sought to determine whether the components of the Notch pathway are expressed in the mouse testis. Western blot analysis revealed the expression of three Notch receptors (Notch 1, Notch 2, and Notch 3), Notch ligands (Jagged 1, Jagged 2, and Delta 1), and presenilin 1 (PS1) in neonatal mouse testis. We then examined their cellular localization by immunohistochemical analysis of cocultures of spermatogonia and Sertoli cells. The 3 Notch receptors were found to be expressed in spermatogonia. Sertoli cells expressed only Notch 2 receptor. Among the Notch ligands, Delta 1 and Jagged 1 were localized exclusively in spermatogonia and Sertoli cells, respectively. PS1 was apparent in both spermatogonia and Sertoli cells. The presence of Notch receptors and Notch ligands in spermatogonia and Sertoli cells indicates that these cells are capable of responding to and eliciting Notch signaling during the process of spermatogenesis. Key words: Cell fate, delta, jagged, presenilin, spermatogenesis.

Animals↗
PubMed2002

Cortisol regulates the expression of Notch in osteoblasts.

Glucocorticoids have important effects on osteoblastic replication, differentiation, and function, and the Notch family of receptors is considered to play a role in osteoblastic cell differentiation. We postulated that cortisol could regulate Notch and Notch ligand expression in osteoblastic cells, providing an additional mechanism by which glucocorticoids could regulate osteoblastic differentiation. We examined the expression and regulation of Notch1, 2, 3, and 4 and their ligands Jagged 1 and 2 and Delta 1 and 3 by cortisol in cultures of osteoblastic MC3T3-E1 cells. Cortisol caused a time-dependent increase in Notch1 and 2 mRNA levels in MC3T3 cells. Notch3 and 4 were not detected in the presence or absence of cortisol. MC3T3 cells expressed Delta 1 and Jagged 1 but not Jagged 2 or Delta 3 mRNAs, and cortisol did not have a substantial effect on the expression of any of these ligands. Cortisol increased the rate of Notch1 and 2 transcription and, in transcriptionally arrested cells, did not modify the decay of the transcripts, indicating a transcriptional level of control. In conclusion, cortisol stimulates Notch1 and 2 transcription in osteoblasts. Since Notch signaling appears to play a negative role in osteoblastic differentiation, its increased expression could be relevant to the actions of cortisol in bone.

Animals↗
PubMed2002

Functional diversity among Notch1, Notch2, and Notch3 receptors.

To clarify functional diversities among the Notch receptors, we generated truncated forms of Notch1, Notch2, and Notch3 comprising the intracellular domain (aN1, aN2, and aN3) and investigated their transcriptional activities for HES1 and HES5 promoters driving the luciferase reporter gene (HES1-Luc and HES5-Luc). The reporter assays demonstrated that the transcriptional activities of aNs were markedly different from each other and dependent on the promoters examined. Furthermore, relative activities between some aN and another for each promoter were altered by the expression level of RBP-J kappa. We also found that the activities of aN1 and aN3 were reduced by coexpression of aN2. These observations suggest that each Notch receptor has a diverse role in the downstream gene expression and that the levels of HES1 and HES5 gene expression are complexly determined by various factors, such as the type and combination of the Notch receptors which confer the downstream signals and the expression level of RBP-J kappa.

Animals↗
PubMed2002

Mouse Notch 3 expression in the pre- and postnatal brain: relationship to the stroke and dementia syndrome CADASIL.

Mutations in the human Notch 3 gene cause the vascular stroke and dementia syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) characterized by degeneration of vascular smooth muscle cells and multiple small infarcts in the white and deep gray matter of the brain. Here we have analyzed the expression pattern of the Notch 3 gene in the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted to a scattered population of cells within the vessel wall of all major blood vessels in the developing embryo, including those that form the perineural vascular plexus. Expression in the postnatal brain is confined to a scattered cell population within the vessel wall of small to medium-sized penetrating arteries, which are the vessel type primarily affected in CADASIL patients. In contrast, no expression was observed in capillaries and veins. Notch 3 is most likely expressed in a subset of vascular smooth muscle cells, and the expression pattern of one of the Notch ligands, Serrate 1, was very similar to that observed for Notch 3. The Notch 3 expressing pattern was not significantly altered in platelet-derived growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that Notch 3 expression is not under direct control of PDGF-B. These data show that Notch 3 expression is conserved between mouse and human and suggest that the mouse is a valid system for analysis of CADASIL.

Animals↗
PubMed1994

Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3.

Cosmid walking of about 250 kb from MHC class III gene CYP21 to class II was conducted. The gene for receptor of advanced glycosylation end products of proteins (RAGE, a member of immunoglobulin superfamily molecules), the PBX2 homeobox gene designated HOX12, and the human counterpart of the mouse mammary tumor gene int-3 were found. The contiguous RAGE and HOX12 genes were completely sequenced, and the human int-3 counterpart was partially sequenced and assigned to a Notch homolog. This human Notch homolog, designated NOTCH3, showed both the intracellular portion present in the mouse int-3 sequence and the extracellular portion absent in the int-3. It thus corresponds to the intact form of a Notch-type transmembrane protein. About 20 kb of dense Alu clustering was found just centromeric to the NOTCH3.

Amino Acid Sequence↗
PubMed1994

The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.

In Drosophila the Notch gene controls differentiation to various cell fates in many tissues. Three mammalian Notch homologs have recently been identified: Notch 1, 2, and 3. All three homologs are very highly conserved relative to the Drosophila Notch gene, which suggests that they are important for cell differentiation in mammals. This notion is supported by the previous finding of a truncated, translocated form of the human NOTCH1 gene (formerly TAN1) in three cases of leukemia. Given this genetic link between NOTCH1 and tumor formation, it is of interest to establish the chromosomal positions of the other two homologs. We report the identification of cosmid clones for the human NOTCH1, 2, and 3 genes. These clones were used as probes in fluorescence in situ hybridization to human metaphase chromosomes, and the results, combined with data from somatic cell hybrid panels, show that the NOTCH2 and 3 genes are located at positions 1p13-p11 and 19p13.2-p13.1, respectively, which are regions of neoplasia-associated translocation.

Amino Acid Sequence↗
PubMed2002

Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression.

Angiogenesis is essential for normal homeostasis, wound healing, and tumor growth and involves a switch in endothelial cell (EC) phenotype from quiescence to migration, proliferation and network formation, and back to quiescence. The notch signaling pathway is critically involved in cell fate decisions during development, and mice deficient in several notch/notch ligand genes have vascular phenotypes. Here we show that notch signaling is activated during EC capillary-like network formation in vitro and that EC express transcripts for notch 1, notch 4, the notch ligand delta 4, and the putative notch processing enzymes ADAM-10 and presenilin. Expression of dominant negative notch blocks network formation; however, constitutively active notch (NICD) does not induce morphologic changes. Furthermore, both EC network formation and expression of activated notch 1 or notch 4 induce expression of the bHLH transcription factor HESR-1 and downregulate the known HESR-1 target VEGFR-2 (KDR). Notch-mediated reduction in VEGFR-2 expression results in decreased EC proliferation in response to VEGF but not bFGF. These data suggest that HESR-1 may be involved in the phenotypic changes that characterize the progression from EC proliferation and migration to network formation and quiescence.

Basic Helix-Loop-Helix Proteins↗
PubMed1995

Clonal variations among multiple primary mammary tumors and within a tumor of individual mice: insertion mutations of int oncogenes.

Laboratory mice infected with the mouse mammary tumor virus (MMTV) often develop multiple mammary tumors. However, no comprehensive studies have been done addressing the question of whether or not different primary tumors of individual mice are related ontogenetically to each other. Further, it is not known to what extent individual tumors vary in their cellular composition. We, therefore, examined intertumor and intratumor patterns of the rearrangements in int-1 (Wnt-1), int-2 (Fgf-3), and int-3 protooncogenes, since mutations in ints caused by MMTV result in the development of mammary tumors in mice and thus provide the most suitable genetic markers for the tumor cells. Our results show that, irrespective of the genetic background of the mice and/or the strain of MMTV, the pattern of MMTV integration in the different tumors of individual mice varies as widely as is found with the tumors of different mice. Of the 79 tumors obtained from 25 mice of different genetic backgrounds, 31 showed insertional mutations in int-1 (39%). By contrast only 9 of the 65 tumors tested had mutations in int-2 (14%). None of the tumors showed mutations in int-3. Interestingly, tumors from individual mice also showed variations in their pattern of int gene mutation, indicating that multiple tumors that develop in a mouse bear no ontogenetical link. The analysis of the pattern of intratumor MMTV integration, int mutation, and int expression revealed that several int mutational events as well as variations in int expression may occur in the same tumor. The diversity of int activation within individual tumors may suggest that the initiation and progression of most mammary tumors, if not all, occur through the concerted action of different mutational events in the same cell or through interactions of different cell populations, each of which acquired different int mutations.

Animals↗
PubMed2000

Identification of a telomeric boundary of the HLA region with potential for predisposition to human narcolepsy.

We report on a study performed to determine a boundary of the region with the potential to contribute to the predisposition to human narcolepsy (the susceptibility region) in the human leukocyte antigen (HLA) region. We investigated a Japanese narcolepsy family, in which a de novo chromosomal recombination occurred between the HLA-DRB1 and HLA-B genes in the proband. The recombinant chromosome carrying HLA-DRB1*1501 was transmitted to the affected child and grandchild, suggesting that a strong genetic factor(s) predisposing to the disorder was (were) present on the chromosome, and that the recombination breakpoint could be regarded as a boundary to the susceptibility region. To search for the breakpoint, we carried out allele typing at various polymorphic sites, e.g., microsatellite repeat polymorphisms, restriction fragment length polymorphisms, and single-nucleotide polymorphisms in the HLA region, and examined haplotypes with the polymorphic sites in the family members. Haplotype analyses revealed that the recombination breakpoint was present approximately 50 kb to the telomeric side of the palmitoyl-protein thioesterase-2 (PPT2) gene in the HLA class III region. From the gene map of the HLA region, the cyclic AMP response element-binding protein-related protein gene (CREB-RP) appeared to be located at the telomeric end in the 50-kb region. Therefore, the data presented here suggest that the susceptibility region for the disorder in the family is present on the centromeric side of the CREB-RP gene in the recombinant Chromosome 6 carrying HLA-DRB1*1501.

Female↗
PubMed1996

Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development.

Notch-like receptors are found in organisms ranging from nematodes to mammals. In Drosophila, Notch plays a key role in cell fate decisions in the early nervous system. In this report we analyse the effects of excess Notch 3 activity in central nervous system (CNS) progenitor cells. A mutated Notch gene encoding the intracellular domain of mouse Notch 3 transcribed from the nestin promoter was expressed in CNS progenitor cells in transgenic mice. This mutation resulted in a phenotypic series of neural tube defects in embryonic day 10.5-12.5 embryos and proved lethal to embryos beyond this age. In the milder phenotype the neural tube displayed a zig-zag morphology and the CNS was slightly enlarged. More severely affected embryos showed a lack of closure of the anterior neural pore, resulting in the externalization of neural tissue and the complete collapse of the third and fourth ventricles. The expanded ventricular zone of the neuroepithelium, a correspondingly enlarged area of nestin expression, and an increase in the number of proliferating cells in the neural tube suggested that these phenotypes resulted from an expanded CNS progenitor cell population. These data provide support in vivo for the notion that Notch activity plays a role in mammalian CNS development and may be required to guide CNS progenitor cells in their choice between continued proliferation or neuronal differentiation.

Animals↗
PubMed2003

Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly stereotyped mutations in the Notch3 receptor. CADASIL is a widespread angiopathy characterized by a degeneration of vascular smooth muscle cells (VSMCs) and the abnormal accumulation of electron-dense granular material called GOM and Notch3 protein, because of an impaired clearance. Evidence that VSMCs are the primary target of the pathogenic process is supported by the restricted expression of Notch3 in these cells but mechanisms of their degeneration remain essentially unknown. We generated transgenic mice in which the SM22alpha promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation. Transgenic mice showed no evidence of prominent brain parenchyma damage but demonstrated the two hallmarks of the CADASIL angiopathy, GOM deposits and Notch3 accumulation, within both the cerebral and peripheral arteries. Of interest, arteries of the tail were more severely affected with prominent signs of VSMC degeneration. Time-course analysis of vessel changes revealed that disruption of normal VSMC anchorage to adjacent extracellular matrix and cells, VSMC cytoskeleton changes as well as starting signs of VSMC degeneration, which were detected around 10 months of age, preceded Notch3 and GOM accumulation appearance, which were observed only by 14 to 16 months of age. In conclusion, we have generated transgenic mice that recapitulate the characteristic vascular lesions observed in CADASIL. Our results indicate that Notch3 or GOM accumulation are unlikely to be the prerequisites for the induction of VSMC degeneration and suggest that degeneration of VSMCs may rather be triggered by the disruption of their normal anchorage, based on the important role of adhesion for cell survival.

Age Factors↗
PubMed2003

Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothelial cells (HUVEC) in fibrin gels: the role of fibroblasts and Angiopoietin-1.

Angiogenesis is a multistep process of critical importance both in development and in physiological and pathophysiological processes in the adult. It involves endothelial cell (EC) sprouting from the parent vessel, followed by migration, proliferation, alignment, tube formation, and anastomosis to other vessels. Several in vitro models have attempted to recreate this complex sequence of events with varying degrees of success. We report an optimized protocol for human umbilical vein EC in which EC sprout from the surface of beads embedded in fibrin gels. Fibroblast-derived factors, other than Angiopoietin-1, promote sprouting, lumen formation, and long-term stability of neovessels. Analysis by time-lapse and still photomicroscopy demonstrates dynamic vessels guided by a "tip cell" that extends numerous processes into the gel. Behind this cell a lumen forms, surrounded by a single layer of polarized EC. The growing sprouts express notch 1, notch 4, and delta 4, as well as the downstream notch effector HESR-1. Importantly, cells can be infected with adenovirus to high efficiency without compromising sprout formation, thus allowing for manipulation of gene expression. This improved model recapitulates all the major steps of angiogenesis seen in vivo and provides a powerful model for analysis of this complex phenomenon.

Adenoviridae↗