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PubMed2002

Refinement of wingless expression by a wingless- and notch-responsive homeodomain protein, defective proventriculus.

Pattern formation during animal development is often induced by extracellular signaling molecules, known as morphogens, which are secreted from localized sources. During wing development in Drosophila, Wingless (Wg) is activated by Notch signaling along the dorsal-ventral boundary of the wing imaginal disc and acts as a morphogen to organize gene expression and cell growth. Expression of wg is restricted to a narrow stripe by Wg itself, repressing its own expression in adjacent cells. This refinement of wg expression is essential for specification of the wing margin. Here, we show that a homeodomain protein, Defective proventriculus (Dve), mediates the refinement of wg expression in both the wing disc and embryonic proventriculus, where dve expression requires Wg signaling. Our results provide evidence for a feedback mechanism that establishes the wg-expressing domain through the action of a Wg-induced gene product.

Animals↗
PubMed1996

Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci.

The human genome contains a group of gene families whose members map within the same regions of chromosomes 1, 6, and 9. The number of gene families involved and their pronounced clustering to the same areas of the genome indicate that their mapping relationship is nonrandom. By combining mapping data and sequence information for the gene families, we have determined that these sequences are part of a large region that spans several megabases. This region is present in three copies: on the long arm of human chromosome 1, the short arm of chromosome 6, and the long arm of chromosome 9. We have characterized the phylogenesis of two of the gene families involved and propose an evolutionary route for the creation of the three regions. Our analysis led us to predict and demonstrate the presence of two loci, a PBX locus on chromosome 6 and a NOTCH locus on chromosome 1. The discovery of this triplicated region increases our understanding of the evolution of the human genome and may have considerable practical implications for gene mapping prediction and novel approaches to isolating new gene family members and uncloned disease loci.

Animals↗
PubMed2005

tantalus, a potential link between Notch signalling and chromatin-remodelling complexes.

The tantalus (tan) gene encodes a protein that interacts specifically with the Polycomb/trithorax group protein Additional sex combs (ASX). Both loss-of-function and gain-of-function mutations in tan cause tissue-specific defects in the eyes, wing veins and bristles of adult flies. As these defects are also typical for components of the Notch (N) signalling pathway, we wished to determine if TAN interacts with this pathway. Through careful examination of ectopic tan phenotypes, we find that TAN specifically disrupts all three major processes associated with the N signalling pathway (boundary formation, lateral inhibition, and lineage decisions). Furthermore, ectopic tan expression abolishes expression of two N target genes, wingless (wg) and cut, at the dorsal-ventral boundary of the wing. An interaction between tan and N was also observed using a genetic assay that previously detected interactions between tan and Asx. The previously observed ability of TAN to move between the cytoplasm and nucleus, and to associate with DNA, provides a potential mechanism for TAN to respond to N signalling.

Animals↗
PubMed2006

The first deltex null mutant indicates tissue-specific deltex-dependent Notch signaling in Drosophila.

Notch (N) is a single-pass transmembrane receptor. The N signaling pathway is an evolutionarily conserved mechanism that controls various cell-specification processes. Drosophila Deltex (Dx), a RING-domain E3 ubiquitin ligase, binds to the N intracellular domain, promotes N's endocytic trafficking to late endosomes, and was proposed to activate Suppressor of Hairless [Su(H)]-independent N signaling. However, it has been difficult to evaluate the importance of dx, because no null mutant of a dx family gene has been available in any organism. Here, we report the first null mutant allele of Drosophila dx. We found that dx was involved only in the subsets of N signaling, but was not essential for it in any developmental context. A strong genetic interaction between dx and Su(H) suggested that dx might function in Su(H)-dependent N signaling. Our epistatic analyses suggested that dx functions downstream of the ligands and upstream of activated Su(H). We also uncovered a novel dx activity that suppressed N signaling downstream of N.

Animals↗
PubMedDate not supplied

Choosing a cell fate: a view from the Notch locus.

During the development of Drosophila melanogaster, individual cells must make choices between a restricted set of possible fates in order to give rise to spatial patterns composed of different types of differentiated cells. The Notch locus appears to play a central and general role in the regulative events that control the local architecture of the final cellular pattern in several tissues, among them being the central and peripheral nervous systems.

Animals↗
PubMed2007

Effects of sulfated hyaluronan on keratinocyte differentiation and Wnt and Notch gene expression.

Sulfated hyaluronan (SHya), which is composed of a sulfated group and hyaluronan (Hya), has high activity on and biocompatibility with cells. When normal human epidermal keratinocytes (NHEKs) were incubated in dishes coated with SHya, cell proliferation was suppressed in a dose-dependent manner. The expression levels of keratin 1 and loricrin mRNAs, as detected by real-time RT-PCR, were increased significantly. The expressions of Wnt mRNAs, which play important roles in cell proliferation and differentiation, were modulated. Wnt4 and Wnt6 mRNA expressions were increased compared to controls, while expression of Wnt5a was similar to the control and that of Wnt7a mRNA was decreased. In addition, the expression of Notch mRNAs, which play a critical role in keratinocyte differentiation, were affected. Notch3 mRNA was increased significantly, while Notch1 mRNA was decreased compared to controls, and expression of Notch2 was similar to that of control. These results suggested that a SHya-coated scaffold might be useful for regulating cell activity in tissue engineering.

Cell Differentiation↗
PubMed2004

Developmental biology: Notching the hindbrain.

One of the best-characterized lineage restrictions in developing vertebrates occurs between adjacent -rhombomeres of the hindbrain. It was recently shown that cells at the boundaries of zebrafish rhombomeres also differ from non-boundary cells in their migratory abilities, a difference driven by Notch signaling.

Animals↗
PubMed2004

Pattern formation: a focus on notch in butterfly eyespots.

New observations of early and dynamic expression of Notch in developing lepidopteran wings suggests that this signalling pathway may function in defining the central focus that will specify the butterfly eyespot colour pattern.

Animals↗
PubMed2004

Nestin expression is lost in a neural stem cell line through a mechanism involving the proteasome and Notch signalling.

Neural stem cells (NSCs) are believed to repair brain damage primarily through cell replacement: i.e., the ability to regenerate lost neurons and glia in a site-specific fashion. The neural stem cell line, MHP36, has been shown to have this capacity, but we have little idea of the molecular mechanisms that control the differentiation of such cells during brain repair. In this study we show that an early event in the differentiation of MHP36 cells, both in vivo and in vitro, is the loss of expression of the intermediate filament protein, nestin. We use a co-culture assay to show that loss of nestin is fast, being detectable after just 1 h and complete in 4 h, and is controlled by proteasome degradation rather than down-regulation of de novo nestin synthesis. We also show that nestin loss is regulated by Notch, and mediated by cell contact.

Acetylcysteine↗
PubMed2005

Cell-cycle control during development: taking it up a notch.

The signals that coordinate cellular proliferation with G1 arrest and differentiation have long been of interest. Two papers in this issue of Developmental Cell show that the conserved Hedgehog and Notch signaling pathways regulate cell division during development of the Drosophila compound eye.

Animals↗
PubMed2005

Closer to the source: notch and the nature of thymus-settling cells.

Questions regarding T cell development have recently received much attention, but the earliest intrathymic differentiation steps in adult mice have remained controversial. Three new papers together show that for at least some thymus-settling precursors, the loss of B lineage potential occurs in the thymus, and Notch acts on multipotent progenitors early after thymic entry.

Animals↗
PubMed2004

The Notch and Sonic hedgehog signalling pathways in immunity.

There is an increasing body of knowledge demonstrating that genes involved in cell fate decisions during development also play a role in the continuous cell fate decisions made by the mature immune system in response to foreign antigen. This review concentrates on the role of the Notch and Sonic hedgehog (Shh) signalling pathways in the development and function of CD4+ T lymphocytes.

Animals↗
PubMed2005

Evidence that nervy, the Drosophila homolog of ETO/MTG8, promotes mechanosensory organ development by enhancing Notch signaling.

In the imaginal tissue of developing fruit flies, achaete (ac) and scute (sc) expression defines a group of neurally-competent cells called the proneural cluster (PNC). From the PNC, a single cell, the sensory organ precursor (SOP), is selected as the adult mechanosensory organ precursor. The SOP expresses high levels of ac and sc and sends a strong Delta (Dl) signal, which activates the Notch (N) receptor in neighboring cells, preventing them from also adopting a neural fate. Previous work has determined how ac and sc expression in the PNC and SOP is regulated, but less is known about SOP-specific factors that promote SOP fate. Here, we describe the role of nervy (nvy), the Drosophila homolog of the mammalian proto-oncogene ETO, in mechanosensory organ formation. Nvy is specifically expressed in the SOP, where it interacts with the Ac and Sc DNA binding partner Daughterless (Da) and affects the expression of Ac and Sc targets. nvy loss- and gain-of-function experiments suggest that nvy reinforces, but is not absolutely required for, the SOP fate. We propose a model in which nvy acts downstream of ac and sc to promote the SOP fate by transiently strengthening the Dl signal emanating from the SOP.

Adaptor Proteins, Signal Transducing↗
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↗
PubMed2001

EGF receptor and Notch signaling act upstream of Eyeless/Pax6 to control eye specification.

The Drosophila compound eye is specified by the concerted action of seven nuclear factors that include Eyeless/Pax6. These factors have been called "master control" proteins because loss-of-function mutants lack eyes and ectopic expression can direct ectopic eye development. However, inactivation of these genes does not cause the presumptive eye to change identity. Surprisingly, we find that several of these eye specification genes are not coexpressed in the same embryonic cells-or even in the presumptive eye. We demonstrate that the EGF Receptor and Notch signaling pathways have homeotic functions that are genetically upstream of the eye specification genes, and show that specification occurs much later than previously thought-not during embryonic development but in the second larval stage.

Animal Structures↗
PubMed1998

Ovarian and breast cytotoxic T lymphocytes can recognize peptides from the amino enhancer of split protein of the Notch complex.

In this study we investigated recognition by ovarian tumor associated lymphocyte (OVTAL), and breast tumor associated lymphocytes (BRTAL), of peptides corresponding to the sequence 125-135 of the Aminoenhancer of split (AES) protein. Three of these peptides designated as G75:AES1/2 (128-135), G60: AES1/2 (127-137) and G61: AES1/2 (125-133) correspond to the wildtype AES sequence, while the fourth G76:GPLTPLPV, AES1/2 (128-135) corresponds to a variant sequence of the peptide G75 with the N-terminal Leu substituted to glycine. These sequences were chosen for study because mass-spectrometric analysis (MS) of a CTL active HPLC peptide fraction eluted from immunoaffinity precipitated HLA-A2 molecule, revealed: (a) the presence of an ion with a mass-to-charge ratio (m/z) of 793 which was more abundant than other ions of similar masses; (b) the tentatively reconstituted sequence of the ion 793 matched the sequence of peptide G76. We found that AES peptides G75 (128-135) and G76 (128-135) (L128G) reconstituted CTL recognition at concentrations ranging between 200-500 nM. These concentrations are lower than concentrations reported to activate effector function of CTL recognizing other epithelial tumor Ag. Furthermore, analysis with cloned CD8+ T cells indicated that G75 and G76 were not cross-reactive specificities, suggesting a key role for the N-terminal residues of the variant peptide in dictating specificities. Since the AES proteins are part of a set of transcriptional repressors encoded by the Enhancer of split [E(spl)] genes, and since these repressors are activated to suppress cell differentiation in response to Notch receptors signalling, the AES peptides may represent a novel class of self-antigens that deserve further consideration as tumor Ag in epithelial cancers.

Antigens, Neoplasm↗
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↗