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PubMed2001

Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt.

Invasive cervical tumors, a major subset of human epithelial neoplasms, are characterized by the consistent presence of papillomavirus oncogenes 16 or 18 E6 and E7 products. Cervical tumors also consistently exhibit cytosolic and nuclear forms of Notch1, suggesting the possible persistent activation of the Notch pathway. Here we show that activated Notch1 synergizes with papillomavirus oncogenes in transformation of immortalized epithelial cells and leads to the generation of resistance to anoikis, an apoptotic response induced on matrix withdrawal. This resistance to anoikis by activated Notch1 is mediated through the activation of PKB/Akt, a key effector of activated Ras in transformation. We suggest that activated Notch signaling may serve to substitute for the lack of activated Ras mutations in the majority of human cervical neoplasms.

Apoptosis↗
PubMed2001

Dynamic expression patterns of the pudgy/spondylocostal dysostosis gene Dll3 in the developing nervous system.

Defects in the Notch pathway ligand Dll3 have been identified in the mouse pudgy (Dll3(pu)) and human spondylocostal dysostosis (SD, MIM 277300) mutations. Although these mutations are primarily associated with segmental defects in the axial skeleton and somitic patterning, they also exhibit cranial neurological defects. Therefore we have looked at the expression of Dll3 in the developing mouse nervous system. The expression of Notch ligands and receptors shares common features at 10.75 dpc in the rhombic lips and dorsal hindbrain. Temporal analysis of Dll3 expression from 9.0 to 11.0 dpc reveals that it is strongly expressed in laminar columns linked with regions of neuronal differentiation and hindbrain segmentation. Transverse sections show that Dll3 is expressed in territories where commissural neurons are formed. We have also looked at neuronal patterning in the mid-hindbrain region in Dll3(pu) mutants.

Animals↗
PubMed2006

Patched1 functions as a gatekeeper by promoting cell cycle progression.

Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.

Animals↗
PubMed1999

Gastrulation in zebrafish: what mutants teach us.

A major approach to the study of development is to compare the phenotypes of normal and mutant individuals for a given genetic locus. Understanding the development of a complex metazoan therefore requires examination of many mutants. Relatively few organisms are being studied this way, and zebrafish is currently the best example of a vertebrate for which large-scale mutagenesis screens have successfully been carried out. The number of genes mutated in zebrafish that have been cloned expands rapidly, bringing new insights into a number of developmental pathways operating in vertebrates. Here, we discuss work on zebrafish mutants affecting gastrulation and patterning of the early embryo. Gastrulation is orchestrated by the dorsal organizer, which forms in a region where maternally derived beta-catenin signaling is active. Mutation in the zygotic homeobox gene bozozok disrupts the organizer genetic program and leads to severe axial deficiencies, indicating that this gene is a functional target of beta-catenin signaling. Once established, the organizer releases inhibitors of ventralizing signals, such as BMPs, and promotes dorsoanterior fates within all germ layers. In zebrafish, several mutations affecting dorsal-ventral (D/V) patterning inactivate genes functioning in the BMP pathway, stressing the central role of this pathway in the gastrula embryo. Cells derived from the organizer differentiate into several axial structures, such as notochord and prechordal mesoderm, which are thought to induce various fates in adjacent tissues, such as the floor plate, after the completion of gastrulation. Studies with mutants in nodal-related genes, in one-eyed pinhead, which is required for nodal signaling, and in the Notch pathway reveal that midline cell fate specification is, in fact, initiated during gastrulation. Furthermore, the organizer coordinates morphogenetic movements, and zebrafish mutants in T-box mesoderm-specific genes help clarify the mechanism of convergence movements required for the formation of axial and paraxial mesoderm.

Animals↗
PubMed2001

Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium.

Notch proteins function as receptors for membrane-bound ligands (Jagged and Delta-like) to regulate cell-fate determination. We have investigated the role of Notch signaling in embryonic endothelium of the mouse by expressing an activated form of the Notch4 protein in vasculature under the regulation of the Flk1 (VEGFR) locus. Expression of activated Notch4 results in a growth and developmental delay and embryonic lethality at about 10 days postcoitum. The extent of the developing vasculature in mutant embryos was restricted, fewer small vessels were seen, and vascular networks were disorganized. The brain periphery of mutant embryos contained large dilated vessels with evidence of compromised vessel-wall integrity and large areas of necrosis; yolk-sac vasculature was abnormal. Expression of an activated form of Notch4 in embryonic vasculature leads to abnormal vessel structure and patterning, implicating the Notch pathway in phases of vascular development associated with vessel patterning and remodeling.

Animals↗
PubMed2005

The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta.

The receptor Notch and its ligands of the Delta/Serrate/LAG2 (DSL) family are the central components in the Notch pathway, a fundamental cell signaling system that regulates pattern formation during animal development. Delta is directly ubiquitinated by Drosophila and Xenopus Neuralized, and by zebrafish Mind bomb, two unrelated RING-type E3 ubiquitin ligases with common abilities to promote Delta endocytosis and signaling activity. Although orthologs of both Neuralized and Mind bomb are found in most metazoan organisms, their relative contributions to Notch signaling in any single organism have not yet been assessed. We show here that a Drosophila ortholog of Mind bomb (D-mib) is a positive component of Notch signaling that is required for multiple Neuralized-independent, Notch-dependent developmental processes. Furthermore, we show that D-mib associates physically and functionally with both Serrate and Delta. We find that D-mib uses its ubiquitin ligase activity to promote DSL ligand activity, an activity that is correlated with its ability to induce the endocytosis and degradation of both Delta and Serrate (see also Le Borgne et al., 2005). We further demonstrate that D-mib can functionally replace Neuralized in multiple cell fate decisions that absolutely require endogenous Neuralized, a testament to the highly similar activities of these two unrelated ubiquitin ligases in regulating Notch signaling. We conclude that ubiquitination of Delta and Serrate by Neuralized and D-mib is an obligate feature of DSL ligand activation throughout Drosophila development.

Animals↗
PubMed2006

T-cell development, doing it in a dish.

The thymus provides a unique environment for the development of T lymphocytes from bone marrow-derived progenitor cells. Several environmental factors have been identified that influence the development of T cells in the thymus. In particular, the Notch pathway has emerged as critical for the induction of T-lineage commitment and differentiation. Until recently, however, the precise nature of the thymus-derived signals that drive T-cell development were unclear, and the only reliable in vitro culture system that supported T-cell differentiation required the use of thymus organ cultures. Here, we discuss recent advances in the identification of critical Notch receptor ligands that have facilitated the development of a simple in vitro model for the differentiation of T cells 'in a dish', providing an alternate approach for studying T lymphopoiesis.

Animals↗
PubMed2006

The GATA2 transcription factor negatively regulates the proliferation of neuronal progenitors.

Postmitotic neurons are produced from a pool of cycling progenitors in an orderly fashion that requires proper spatial and temporal coordination of proliferation, fate determination, differentiation and morphogenesis. This probably relies on complex interplay between mechanisms that control cell cycle, specification and differentiation. In this respect, we have studied the possible implication of GATA2, a transcription factor that is involved in several neuronal specification pathways, in the control of the proliferation of neural progenitors in the embryonic spinal cord. Using gain- and loss-of-function manipulations, we have shown that Gata2 can drive neural progenitors out of the cycle and, to some extent, into differentiation. This correlates with the control of cyclin D1 transcription and of the expression of the p27/Kip1 protein. Interestingly, this functional aspect is not only associated with silencing of the Notch pathway but also appears to be independent of proneural function. Consistently, GATA2 also controls the proliferation capacity of mouse embryonic neuroepithelial cells in culture. Indeed, Gata2 inactivation enhances the proliferation rate in these cells. By contrast, GATA2 overexpression is sufficient to force such cells and neuroblastoma cells to stop dividing but not to drive either type of cell into differentiation. Furthermore, a non-cell autonomous effect of Gata2 expression was observed in vivo as well as in vitro. Hence, our data have provided evidence for the ability of Gata2 to inhibit the proliferation of neural progenitors, and they further suggest that, in this regard, Gata2 can operate independently of neuronal differentiation.

Animals↗
PubMed2003

Mechanisms of neuroendocrine differentiation in pulmonary neuroendocrine cells and small cell carcinoma.

We review the significance of a network of proneural basic helix-loop-helix (bHLH) factors. Immunohistochemically, pulmonary neuroendocrine cells (PNECs) are positive for Mash1, one of the activator bHLHs, and non-PNECs such as Clara cells are positive for Hes1, one of the repressor bHLHs. Since mice deficient for the Mash1 gene do not possess PNEC and mice deficient for the Hes1 gene have many PNECs, it is suggested that a network of bHLHs work in cell fate determination of lung epithelium. Moreover, the Notch pathway could play a role in cell differentiation mechanisms in the lung because this signaling pathway has been reported to work in various tissues. PNECs have been reported to modulate various nonneoplastic human lung diseases. We demonstrate that PNECs in usual interstitial pneumonia and hASH1 (human homolog of Mash1) are upregulated in diseased lung tissues. Moreover, studies of small cell carcinoma and non- small cell carcinoma suggest that neuroendocrine differentiation could be regulated by hASH1. In non-small cell carcinoma, Hes1 and Notch signaling may have roles in maintaining cell differentiation. Thus, a network of bHLHs and Notch signaling are important in cell differentiation of normal and pathologic lung epithelial cells.

Animals↗
PubMed2004

Expression of zebrafish six1 during sensory organ development and myogenesis.

Drosophila sine oculis homologous genes in vertebrates are homeobox-containing transcription factors functioning within the Pax-Six-Eya-Dach regulatory network during development. In this study, we describe the cloning and expression of a zebrafish homolog of sine oculis, six1. The reverse transcription-polymerase chain reaction demonstrated accumulation of six1 transcripts at mid-gastrula, and in situ hybridization showed their subsequent expression in the cranial placode and later in the olfactory, otic, and lateral line placodes, inner ear, and neuromasts. In addition, six1 is expressed in the pituitary, branchial arches, somites, pectoral fin, ventral abdomen muscle, and the cranial muscles of the eye and lower jaw. An increase of six1 expression was observed in the lateral line, muscles, and inner ear of the mind bomb mutant, illustrating a regulatory effect of the Notch pathway on expression of Six genes.

Amino Acid Sequence↗
PubMed1995

Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch.

The first cells generated during development of the vertebrate retina are the ganglion cells, the projection neurons of the retina. Although they are one of the most intensively studied cell types within the central nervous system, little is known of the mechanisms that determine ganglion cell fate. We demonstrate that ganglion cells are selected from a large group of competent progenitors that comprise the majority of the early embryonic retina and that differentiation within this group is regulated by Notch. Notch activity in vivo was diminished using antisense oligonucleotides or augmented using a retrovirally transduced constitutively active allele of Notch. The number of ganglion cells produced was inversely related to the level of Notch activity. In addition, the Notch ligand Delta inhibited retinal progenitors from differentiating as ganglion cells to the same degree as did activated Notch in an in vitro assay. These results suggest a conserved strategy for neurogenesis in the retina and describe a versatile in vitro and in vivo system with which to examine the action of the Notch pathway in a specific cell fate decision in a vertebrate.

Alleles↗
PubMed2004

Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer.

Achaete-scute homolog-1 (termed Mash1 in rodents, hASH1 in humans) is a basic helix-loop-helix transcription factor important in early development of neural and neuroendocrine (NE) progenitor cells in multiple tissues including the CNS, autonomic nervous system, adrenal medulla, thyroid, lung, and prostate, among others. This review discusses how progress in developmental neurobiology of Mash1 has translated into novel insights in NE tumor biology, particularly for small cell lung cancer. Inhibition of this factor by the Notch pathway is essential in regulating NE commitment in airway epithelial precursor cells, and may play a comparable role in modulating phenotypes of lung cancer and other tumors.

Animals↗
PubMed2006

Neural stem cell properties of Müller glia in the mammalian retina: regulation by Notch and Wnt signaling.

The retina in adult mammals, unlike those in lower vertebrates such as fish and amphibians, is not known to support neurogenesis. However, when injured, the adult mammalian retina displays neurogenic changes, raising the possibility that neurogenic potential may be evolutionarily conserved and could be exploited for regenerative therapy. Here, we show that Müller cells, when retrospectively enriched from the normal retina, like their radial glial counterparts in the central nervous system (CNS), display cardinal features of neural stem cells (NSCs), i.e., they self-renew and generate all three basic cell types of the CNS. In addition, they possess the potential to generate retinal neurons, both in vitro and in vivo. We also provide direct evidence, by transplanting prospectively enriched injury-activated Müller cells into normal eye, that Müller cells have neurogenic potential and can generate retinal neurons, confirming a hypothesis, first proposed in lower vertebrates. This potential is likely due to the NSC nature of Müller cells that remains dormant under the constraint of non-neurogenic environment of the adult normal retina. Additionally, we demonstrate that the mechanism of activating the dormant stem cell properties in Müller cells involves Wnt and Notch pathways. Together, these results identify Müller cells as latent NSCs in the mammalian retina and hence, may serve as a potential target for cellular manipulation for treating retinal degeneration.

Animals↗
PubMed1999

Identification and expression of a novel family of bHLH cDNAs related to Drosophila hairy and enhancer of split.

In this report we describe the initial characterization of murine, human, and Drosophila hesr-1 (for hairy and enhancer of split related-1) a novel evolutionary conserved family of hairy/enhancer of split homologs. Hesr-1 cDNAs display features typical of hairy and enhancer of split-type bHLH proteins including a N-terminal bHLH domain a conserved orange domain immediately C-terminal to the bHLH region. Despite their similarity to known hairy/enhancer of split homologs, hesr-1 cDNAs are divergent members of the hairy and enhancer of split bHLH family since the degree of sequence identity within the bHLH and their nearest homologs are relatively low. Moreover, the tetrapeptide motif, WRPW, which is found in all hairy and enhancer of split family members, is not present in hesr-1. Rather, a variant of this motif, YRPW, is found. Analysis of embryonic murine hesr-1 expression by in situ hybridization reveals strong expression in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs indicating a role for hesr-1 in the development of these tissues. Like the enhancer of split cDNAs in Drosophila, we show that hesr-1 expression depends critically on signaling through the notch pathway in murine embryos, suggesting that aspects of hesr-1 regulation and function might also be evolutionary conserved.

Amino Acid Sequence↗
PubMed2004

Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling.

Basic fibroblast growth factor (FGF2)-responsive definitive neural stem cells first appear in embryonic day 8.5 (E8.5) mouse embryos, but not in earlier embryos, although neural tissue exists at E7.5. Here, we demonstrate that leukemia inhibitory factor-dependent (but not FGF2-dependent) sphere-forming cells are present in the earlier (E5.5-E7.5) mouse embryo. The resultant clonal sphere cells possess self-renewal capacity and neural multipotentiality, cardinal features of the neural stem cell. However, they also retain some nonneural properties, suggesting that they are the in vivo cells' equivalent of the primitive neural stem cells that form in vitro from embryonic stem cells. The generation of the in vivo primitive neural stem cell was independent of Notch signaling, but the activation of the Notch pathway was important for the transition from the primitive to full definitive neural stem cell properties and for the maintenance of the definitive neural stem cell state.

Animals↗
PubMed2005

Notch-dependent downregulation of the homeodomain gene cut is required for the mitotic cycle/endocycle switch and cell differentiation in Drosophila follicle cells.

During Drosophila mid-oogenesis, follicular epithelial cells switch from the mitotic cycle to the specialized endocycle in which the M phase is skipped. The switch, along with cell differentiation in follicle cells, is induced by Notch signaling. We show that the homeodomain gene cut functions as a linker between Notch and genes that are involved in cell-cycle progression. Cut was expressed in proliferating follicle cells but not in cells in the endocycle. Downregulation of Cut expression was controlled by the Notch pathway and was essential for follicle cells to differentiate and to enter the endocycle properly. cut-mutant follicle cells entered the endocycle and differentiated prematurely in a cell-autonomous manner. By contrast, prolonged expression of Cut caused defects in the mitotic cycle/endocycle switch. These cells continued to express an essential mitotic cyclin, Cyclin A, which is normally degraded by the Fizzy-related-APC/C ubiquitin proteosome system during the endocycle. Cut promoted Cyclin A expression by negatively regulating Fizzy-related. Our data suggest that Cut functions in regulating both cell differentiation and the cell cycle, and that downregulation of Cut by Notch contributes to the mitotic cycle/endocycle switch and cell differentiation in follicle cells.

Animals↗
PubMed2002

Characterization of the transcriptional expression of Notch-1 signaling pathway members, Deltex and HES-1, in developing mouse thymocytes.

The Notch transmembrane protein is involved in a broad range of different developmental pathways in vertebrates and invertebrates. Targeted thymocyte expression of the Notch-1 intracellular domain has been shown to affect lineage commitment decisions such as those involving T cell vs. B cell, thymocyte alpha beta vs. gamma delta TCR, as well as CD4 vs. CD8 thymocyte commitment. In this paper, we quantitatively characterize thymocyte RNA expression of two purported transcriptional markers of Notch-1 signaling activity, Deltex and HES-1. Using a semiquantitative RTPCR approach, we show that both Deltex and HES-1 transcriptional levels are developmentally regulated as thymocytes mature from the earliest CD4/CD8 double negative thymocyte stage, through the intermediate CD4/CD8 double positive stage, and finally to the mature CD4 or CD8 single positive stage. Deltex and HES-1, despite both being transcriptional markers of Notch-1 activity, express different patterns of transcriptional activity among the thymocyte subsets. Neither treatment with combined (alpha CD3)/(alpha CD28) antibodies nor the combination of the phorbol ester PMA and calcium ionophore ionomycin affects expression of Deltex in immature thymocytes; however, PMA/ionomycin treatment does downregulate expression of HES-1, an affect mostly mediated by ionomycin. Finally, a difference in HES-1 expression is seen between CD4/CD8 double positive thymocytes isolated from wild-type vs. MHC class I/II deficient mice, suggesting that Notch-1 activity is modulated during in vivo TCR/MHC-ligand selection events.

Animals↗
PubMed2003

Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells.

Following activation by antigen, naive CD4+ T helper precursor cells execute distinct genetic programs that result in their differentiation toward the type 1 or type 2 helper T cell (Th1 or Th2) phenotype. Although the differentiation and function of these Th subsets has been well studied, little is known about the contribution to these differentiation events of cell surface receptors other than those for soluble cytokines, such as IL-12 or IL-4. Here, we provide direct evidence that the Delta1 interaction with Notch3 on CD4+ T cells transduces signals, promoting development toward the Th1 phenotype. The positive role of Notch signaling in effector cell differentiation was dose dependent, with high levels of stimulation resulting in reduced T cell activation. Our data revealed a clear contribution of Notch pathways to Th1 versus Th2 fate decisions, while also providing insight into another mechanism for inhibition of CD4+ T cell activation.

Animals↗