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PubMed2002

Differential expression of Notch genes in human osteoblastic cells.

Notch receptors participate in a conserved signaling pathway that controls the development of diverse tissues and cell types. In the present study we investigated the expression of four Notch genes in primary human osteoblasts and in human osteoblastic osteosarcoma cell line SaOS-2 by RT-PCR. We found a strong constitutive expression of Notch-1 and a weak constitutive expression of Notch-2 in both cell types. After stimulation with Dexamethasone or Vitamin D(3), two factors known to induce differentiation in osteogenic cells, both Notch receptors were downregulated, however, with a different time course. Notch-1 and Notch-2 showed a transient induction after 2 days and a decrease after 7 days in osteoblasts and after 28 days in SaOS-2 cells. Notch-4 expression could only be detected after stimulation with Dexamethasone and Vitamin D(3). However, in osteoblasts a transient induction after 2 days could be detected in osteoblasts, whereas Notch-4 expression increased after 14 and 28 days in SaOS-2 cells. In contrast, Notch-3 was not expressed in human osteoblasts and SaOS-2 osteosarcoma cells. These data show, that Notch genes are expressed in human osteoblastic cells and that the expression is differentially regulated upon stimulation with osteogenic factors.

Cell Differentiation↗
PubMed1999

Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds.

Strikingly increased expression of notch-1 has been demonstrated in several human malignancies and pre-neoplastic lesions. However, the functional consequences of notch-1 overexpression in transformed cells remain unclear. We investigated whether endogenously expressed notch-1 controls cell fate determination in mouse erythroleukemia (MEL) cells during pharmacologically induced differentiation. We found that notch-1 expression is modulated during MEL cell differentiation. Premature downregulation of notch-1 during differentiation, by antisense S-oligonucleotides or by enforced expression of antisense notch-1 mRNA, causes MEL cells to abort the differentiation program and undergo apoptosis. Downregulation of notch-1 expression in the absence of differentiation inducer increases the likelihood of spontaneous apoptosis. We conclude that in MEL cells, endogenous notch-1 expression controls the apoptotic threshold during differentiation and growth. In these cells, notch-1 allows differentiation by preventing apoptosis of pre-committed cells. This novel function of notch-1 may play a role in regulating apoptosis susceptibility in notch-1 expressing tumor cells.

Acetamides↗
PubMedDate not supplied

Requirement of Notch 1 and its ligand jagged 2 expressions for spermatogenesis in rat and human testes.

It has already been demonstrated that the Notch signaling system is essential for gametogenesis in the adult germ line of Caenorhabditis elegans. However, the role of the Notch signaling system in mammalian spermatogenesis has not been well investigated. Recently, it has been revealed that this signaling system is expressed in the mammalian testis by showing coexpression of Jagged 2 and its receptor, Notch 1, is consistent with Notch 1 being a cognate receptor for Jagged 2 in the mammalian testis. Therefore, we investigated expressions of messenger RNAs of Notch 1 and Jagged 2 in the testicular tissues of developing Sprague-Dawley rats by reverse transcription-polymerase chain reaction and Northern blot analysis, expressions of their proteins in the testicular tissues of developing rats, fertile human controls and infertile human patients with maturation arrest by immunohistochemistry, and effects of antibodies to this system by culturing rat testicular tissues with these antibodies. Transcripts of Notch 1 and Jagged 2 in the rat testis were positive throughout the examined period; these intensities became higher at day 13 after birth, coincidence with the formation of spermatocytes, and peaked at day 19 after birth. Expressions of Notch 1 and Jagged 2 were recognized at first in the perinuclear regions of spermatocytes in the rat testis as a round structure at day 19 after birth and thereafter in further differentiated germ cells as meiosis proceeded. In the adult rat testis, positive staining was present as a round structure in spermatocytes, as a typical horseshoe-shaped structure in round spermatids, and as a covering structure spreading around the nucleus of elongated spermatids, but not in spermatozoa. Notch 1 was recognized in the vacuole of the Golgi complex of primary spermatocytes and the acrosome of elongated spermatids with electron microscopy. When rat testicular tissues were cultured with anti-Notch 1 or anti-Jagged 2 antibody, round and elongated spermatids decreased after 5 and 7 days of culture, respectively, and disappeared at around 9 and 12 days of culture, respectively, with shrinkage of the diameter of seminiferous tubules. Spermatocytes, however, increased after 11 days of culture. Expressions of both proteins have been detected in the testicular tissues of human fertile controls as in the rat testicular tissues. However, Notch 1 expression has not been detected in testicular tissues of 11 patients with maturation arrest, whereas Jagged 2 expression has been recognized in all of them. In conclusion, the results presented in this study offer the possibility that Notch 1/Jagged 2 signaling system plays an important role for male germ cells to differentiate or at least to survive in the rat testis and fails to express in the testis of spermatogenic maturation arrest patients.

Actins↗
PubMed2004

Characterization of tissue specific expression of Notch-1 in human tissues.

Signaling through the Notch cell surface receptors is a highly conserved mechanism of cell fate specification. Notch signaling regulates proliferation, differentiation and cell death. In vertebrates, putative gene duplication has originated four Notch genes, Notch-1, -2, -3 and -4. They have been implicated in neurogenesis, hematopoiesis, T-cell development, vasculogenesis and brain cortical growth. We have investigated Notch-1 distribution in normal human tissues by immunohistochemistry and immunoblot. We detected widespread expression of Notch-1 cytoplasmatic staining, with different tissue distributions in the different organs examined. In particular, high expression of Notch-1 was detected in the intermediate suprabasal layers, but not in the dead cells at the extreme periphery of stratified epithelia. Moreover, a low/intermediate level of Notch-1 was observed in lymphocytes in several peripheral lymphoid tissues; in particular the germinal centers of lymph nodes showed the most abundant number of positive cells, which appeared to be centroblasts/immunoblasts based on nuclear morphology. Notch-1 participates in keratinocytes differentiation. We showed by Western blot analysis that Notch-1 level was clearly increased in HaCaT cells after Ca(++) addition and remained substantially elevated until late differentiation stages. These results suggest that Notch-1 may function in numerous cell types in processes beyond cell fate determination, such as neuronal plasticity, muscle hypertrophy, liver regeneration, and germinal center lymphopoiesis during the immune response.

Blotting, Western↗
PubMed1995

Relation between aortic dicrotic notch pressure and mean aortic pressure in adults.

It has recently been suggested that mean arterial pressure provides a reliable estimate of dicrotic notch pressure in infants and children. The aim of the present study was twofold: (1) to investigate the relation existing between aortic dicrotic notch pressure and both the steady and pulsed component of aortic pressure in adults (i.e., mean and pulse aortic pressures, respectively); and (2) to evaluate mean aortic pressure as an estimate of aortic dicrotic notch pressure. High-fidelity pressure recordings were obtained at the aortic root level in 17 men (52 +/- 13 years). Pressure data were analyzed at rest over 10 consecutive beats in each patient, and, in 6 patients, during the Valsalva maneuver (over 22 to 50 consecutive beats). At rest, dicrotic notch pressure was greater than mean pressure (109.0 +/- 17.9 vs 99.6 +/- 12.5 mm Hg, p = 0.0001). Dicrotic notch pressure was positively related to mean pressure (r = 0.93) and to pulse pressure (r' = 0.77), but not to patient's heart rate, cardiac output, or total estimated arterial compliance. There was a spontaneous beat-to-beat relation between dicrotic notch and mean pressures (1) at rest in 16 of 17 patients (mean r = 0.85), and (2) in all patients undergoing the Valsalva maneuver (mean r = 0.97). During the maneuver, intravascular mean pressure ranged from 59 to 171 mm Hg. Dicrotic notch pressure was positively related to mean pressure (r = 0.98) and to pulse pressure (r' = 0.44). Both at rest and during the Valsalva maneuver, mean pressure underestimated dicrotic notch pressure, and the higher the dicrotic notch pressure, the more negative the percent error (each p = 0.0001). In conclusion, aortic dicrotic notch pressure was mainly related to the steady component of aortic pressure. The mean aortic pressure slightly but significantly underestimated aortic dicrotic notch pressure, and thus should be used with greater caution in adults than in young patients as an estimate of end-systolic pressure.

Adult↗
PubMed2005

Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis.

BACKGROUND & AIMS: Inflammatory mediators and cell fate genes, such as the Notch gene family, both have been implicated in cancer biology. Because cholangiocarcinomas arise in a background of inflammation and express the inflammatory mediator inducible nitric oxide synthase (iNOS), we aimed to determine whether iNOS expression alters Notch expression and signaling. METHODS: Notch receptor and ligand expression in human liver was evaluated by immunohistochemistry. The effect of iNOS and NO on Notch-1 expression was examined in cell lines. RESULTS: Notch-1, but not other Notch receptors, were up-regulated by cholangiocytes in primary sclerosing cholangitis and cholangiocarcinoma. The colocalization of Notch-1 and iNOS also was observed in large bile ducts from the hilar region of primary sclerosing cholangitis patients. Notch-1 expression in murine cholangiocytes was iNOS dependent. iNOS expression also facilitated Notch signaling by inducing the nuclear translocation of its intracellular domain and the expression of a transcriptional target, hairy and enhancer of split (Hes)-1. The gamma-secretase inhibitor N-[N-(3,5-Difluorophenacetyl-L-alanyl)-S-phenylglycine]-t-butyl ester, which blocks Notch signaling, enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cholangiocarcinoma cells. CONCLUSIONS: These data implicate a direct link between the inflammatory mediator iNOS and Notch signaling, and have implications for the development and progression of cholangiocarcinoma.

Adenocarcinoma↗
PubMed2006

Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells.

Pancreatic cancer remains the fourth most common cause of cancer-related death in the United States. Notch signaling plays a critical role in maintaining the balance among cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of pancreatic cancer. To characterize Notch pathway function in pancreatic cancer cells, we explored the consequences of down-regulation of Notch-1 in BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. Using multiple cellular and molecular approaches such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis assay, flow cytometry, gene transfection, real-time reverse transcription-PCR (RT-PCR), Western blotting, and electrophoretic mobility shift assay for measuring DNA binding activity of nuclear factor kappaB (NF-kappaB), we found that down-regulation of Notch-1 inhibited cell growth and induced apoptosis in pancreatic cancer cells. Notch-1 down-regulation also increased cell population in the G(0)-G(1) phase. Compared with control, small interfering RNA-transfected cells decreased expression of cyclin A, cyclin D1, and cyclin-dependent kinase 2. We found up-regulation of p21 and p27, which was correlated with the cell cycle changes. In addition, Notch-1 down-regulation also induced apoptosis, which could be due to decreased Bcl-2 and Bcl-X(L) protein expression in pancreatic cancer cells. Because Notch-1 is known to cross-talk with another major cell growth and apoptotic regulatory pathway (i.e., NF-kappaB), we found that NF-kappaB is a downstream target of Notch because down-regulation of Notch reduced NF-kappaB activity. We also found that genistein, a prominent isoflavone, could be an active agent for the down-regulation of the Notch pathway. These findings suggest that Notch-1 down-regulation, especially by genistein, could be a novel therapeutic approach for the treatment of pancreatic cancer.

Antineoplastic Agents↗
PubMedDate not supplied

Symmetry of the femoral notch width index.

A small femoral notch width index has been reported as a predictive factor for anterior cruciate ligament injury and implicated in the higher incidence of anterior cruciate ligament injuries in female athletes. Notch-plasty has been recommended for the unaffected knees of patients who have torn one anterior cruciate ligament and whose notch width index falls one standard deviation below "normal". However, the symmetry of the notch width index has not been specifically studied. We compared the notch width index in both knees of 40 male and 40 female patients. Half of the patients in each group had anterior cruciate ligament injuries, all from a noncontact mechanism. We found that the notch width indexes of the right and left knees of the same patient are essentially symmetrical, regardless of sex or anterior cruciate ligament status. Although the female patients tended to have smaller notch width indexes than the male patients, the difference was not statistically significant. Moreover, the ranges of notch width indexes in male and female patients overlapped considerably. Finally, there was no difference in notch width index between patients with and without anterior cruciate ligament tears. These findings suggest that the notch width index alone is not the critical etiologic factor in the patient with a unilateral anterior cruciate ligament tear. Furthermore, the increased incidence of anterior cruciate ligament tears in female patients compared with male patients in the same sports cannot be attributed to notch width index alone.

Adult↗
PubMed1989

The expression of the neurogenic locus Notch during the postembryonic development of Drosophila melanogaster and its relationship to mitotic activity.

The molecular analysis of the Notch locus of Drosophila melanogaster demonstrated that it codes for a protein which shows homology to the epidermal growth factor as well as to the products of certain yeast genes involved in the control of the cell cycle (Wharton et al., 1985a; Breeden and Nasmyth, 1987). The structure of the protein suggests that Notch is involved in a cell interaction mechanism which controls the differentiation of several different tissues during development. Here we examine Notch expression during imaginal development using in situ hybridization to tissue sections and demonstrate that Notch is not expressed ubiquitously during the postembryonic stages, but rather is confined to specific tissues. During the larval and early pupal period Notch transcripts are predominantly localized in the imaginal discs and the central nervous system. In the middle and late pupal period the signal levels in these tissues drop dramatically and in the adult animal Notch transcripts are essentially detected only in the ovaries. In the larval stages the pattern of Notch expression appears to be closely correlated with mitotically active tissues, while in later stages this correlation appears less strict. The findings reported here indicate that there is a requirement for normal Notch function in a number of tissues at several developmental stages and that the pleiotropic phenotypic manifestation of Notch mutations is a context dependent developmental result. The observed association of Notch expression with mitotically active cell populations raises the possibility that Notch may play a role in the cell cycle.

Animals↗
PubMed2001

Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain.

Notch participates in diverse cell fate decisions throughout embryonic development and postnatal life. Members of the NF-kappaB/Rel family of transcription factors are involved in the regulation of a variety of genes important for immune function. The biological activity of the NF-kappaB transcription factors is controlled by IkappaB proteins. Our previous work demonstrated that an intracellular, constitutively active form of human Notch-1/translocation-associated Notch homologue-1 (Notch(IC)) functions as an IkappaB molecule with specificity for the NF-kappaB p50 subunit and physically interacts with NF-kappaB in T cells. In the current study, we investigated the roles of different domains of Notch(IC) in the regulation of NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. We found that Notch(IC) localizes to the nucleus and that a region in the N-terminal portion of Notch(IC), not the six ankyrin repeats, is responsible for the inhibitory effects of Notch on NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. The N-terminal portion of Notch(IC) inhibited p50 DNA binding and interacted specifically with p50 subunit, not p65 of NF-kappaB. The interaction between Notch and NF-kappaB indicates that in addition to its role in the development of the immune system, Notch-1 may also have critical functions in the immune response, inflammation, viral infection, and apoptosis through control of NF-kappaB-mediated gene expression.

Amino Acid Sequence↗
PubMed1998

A morphological study of the fetal ilium; focusing on the sexual differences of the greater sciatic notch.

A number of studies on sexual differences in the ilium have been reported. However, most of these studies have focused on the adult ilium. With regard to sexual differences in the fetal ilium, few studies have been carried out. Especially, there have few studies regarding sexual differences in the fetal ilium using dry bones. In the present study, sexual differences in the morphological characteristics of the greater sciatic notch were investigated using dry fetal iliac bones. We examined 212 fetuses (106 males and 106 females) measuring 20.0 cm or more in fetal length with free of gross malformations or deformities which were collected at Saga Medical School. The iliac bones were excised from these fetuses and dried as materials for study. Fetal length was measured in the fully extended position and was classified into six groups each for males and females in 5-cm increments, giving a total of twelve groups. The inner lateral surface of the greater sciatic notch was magnified 25x using projector, traced, and the tracings were inputted to a computer (7600/120: Apple Co. Ltd) using a flatbed scanner. The width and height of the greater sciatic notch were measured, as well as the area of the greater sciatic notch. No sexual differences were noted regarding the increase in the width of the greater sciatic notch in fetuses up to 39.9 cm in fetal length. In fetuses measuring between 40.0 anf 44.9 cm, a significant sexual difference was observed, with the increase in greater sciatic notch width markedly greater in females. With respect to the increase in the height of the greater sciatic notch, no significant differences were noted. No significant differences were observed in the total area of the greater sciatic notch in fetuses up to 39.9 cm in fetal length. On the other hand, a significant sexual difference was observed in fetuses measuring 40.0 cm or more, with the total area markedly increased in females. In addition, no significant differences were found in the area between the two sides of the greater sciatic notch in fetuses up to 39.9 cm in fetal length, although significant differences were observed in fetuses measuring 40.0 cm or more. In female fetuses 40.0 cm or more in fetal length, the greater sciatic notch was found to be wider than in males, and the peak of the greater sciatic notch was displaced in the anteroinferior direction, farther from the auricular surface of the ilium and nearer the pubic bone. Thus these female fetuses show morphological characteristics of the adult female pelvic bone. Based on the results obtained, it is concluded that sexual differences can be identified in fetuses from the 8th month of pregnancy (fetal length 40.0 cm or more).

Anthropometry↗
PubMed2003

HES and HERP families: multiple effectors of the Notch signaling pathway.

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Multiple factors at each step-ligands, receptors, signal transducers and effectors-play critical roles in executing the pleiotropic effects of Notch signaling. Ligand-binding results in proteolytic cleavage of Notch receptors to release the signal-transducing Notch intracellular domain (NICD). NICD migrates into the nucleus and associates with the nuclear proteins of the RBP-Jkappa family (also known as CSL or CBF1/Su(H)/Lag-1). RBP-Jkappa, when complexed with NICD, acts as a transcriptional activator, and the RBP-Jkappa-NICD complex activates expression of primary target genes of Notch signaling such as the HES and enhancer of split [E(spl)] families. HES/E(spl) is a basic helix-loop-helix (bHLH) type of transcriptional repressor, and suppresses expression of downstream target genes such as tissue-specific transcriptional activators. Thus, HES/E(spl) directly affects cell fate decisions as a primary Notch effector. HES/E(spl) had been the only known effector of Notch signaling until a recent discovery of a related but distinct bHLH protein family, termed HERP (HES-related repressor protein, also called Hey/Hesr/HRT/CHF/gridlock). In this review, we summarize the recent data supporting the idea of HERP being a new Notch effector, and provide an overview of the similarities and differences between HES and HERP in their biochemical properties as well as their tissue distribution. One key observation derived from identification of HERP is that HES and HERP form a heterodimer and cooperate for transcriptional repression. The identification of the HERP family as a Notch effector that cooperates with HES/E(spl) family has opened a new avenue to our understanding of the Notch signaling pathway.

Animals↗
PubMed1999

Wingless modulates the effects of dominant negative notch molecules in the developing wing of Drosophila.

The development and patterning of the wing in Drosophila relies on a sequence of cell interactions molecularly driven by a number of ligands and receptors. Genetic analysis indicates that a receptor encoded by the Notch gene and a signal encoded by the wingless gene play a number of interdependent roles in this process and display very strong functional interactions. At certain times and places, during wing development, the expression of wingless requires Notch activity and that of its ligands Delta and Serrate. This has led to the proposal that all the interactions between Notch and wingless can be understood in terms of this regulatory relationship. Here we have tested this proposal by analysing interactions between Delta- and Serrate-activated Notch signalling and Wingless signalling during wing development and patterning. We find that the cell death caused by expressing dominant negative Notch molecules during wing development cannot be rescued by coexpressing Nintra. This suggests that the dominant negative Notch molecules cannot only disrupt Delta and Serrate signalling but can also disrupt signalling through another pathway. One possibility is the Wingless signalling pathway as the cell death caused by expressing dominant negative Notch molecules can be rescued by activating Wingless signalling. Furthermore, we observe that the outcome of the interactions between Notch and Wingless signalling differs when we activate Wingless signalling by expressing either Wingless itself or an activated form of the Armadillo. For example, the effect of expressing the activated form of Armadillo with a dominant negative Notch on the patterning of sense organ precursors in the wing resembles the effects of expressing Wingless alone. This result suggests that signalling activated by Wingless leads to two effects, a reduction of Notch signalling and an activation of Armadillo.

Animals↗
PubMed2001

Expression of notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients.

Notch is known as a receptor that controls differentiation or proliferation in various cells and is associated with several diseases. The objective of the present study was to clarify whether human Notch homologues Notch-1, -2, -3, and -4 are expressed in synovium and synoviocytes from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Immunohistochemical staining showed that Notch-1, -2, and -3 were clearly expressed in the synovium from both RA and OA, whereas Notch-4 was only slightly detected. We further performed Western blotting with the same antibodies used in immunohistochemical staining. Notch-1 and -2 were strongly detected in both RA and OA, and the expression of Notch-3 was slightly detected, while there was no Notch-4 expression in both RA and OA synoviocytes. In contrast, all Notch homologues were strongly expressed in the synovium at the developmental stage obtained from the infant. These results indicate that the expression pattern of Notch among synovium from OA and RA patients differed from that of normal subjects.

Adult↗
PubMed2006

Methylmercury induces activation of Notch signaling.

Methylmercury (MeHg) toxicity in humans manifests deficits in neurological function. Cases of prenatal exposure to mercury have established that the developing nervous system is most highly susceptible to perturbation by MeHg. At a cellular level, MeHg-induced defects result from altered neuronal proliferation, migration and pathfinding. However, the molecular targets of MeHg that give rise to these outcomes are not fully understood. In an overall effort to identify the fundamental molecular targets of MeHg in neural development, we have explored the effects of MeHg on cell surface receptor function using the simplified Drosophila model. In this study, we investigated the potential role of MeHg to alter activity of the Notch receptor pathway, a highly conserved cell-cell signaling mechanism that controls cell fate decisions, proliferation, migration and neurite outgrowth in neural development. Notch receptor activation requires proteolysis by a cell surface ADAM metalloprotease. ADAM proteases are required for normal neural development and are activated by organomercurials, thus presenting a possible mechanism for MeHg neurotoxicity. Here, we demonstrate a concentration- and time-dependent increase in Notch receptor activity with MeHg exposure in three distinct Drosophila cell lines. Ten micromolar MeHg results in a 4-5.5-fold increase in Notch signaling as measured by the upregulation of two enhancer of split (E(spl)) target genes. MeHg-induced Notch activity also correlates with receptor proteolysis. Targeted knockdown of Notch protein expression demonstrates that MeHg induced E(spl) activation specifically requires the Notch receptor. Furthermore, MeHg-induced Notch activity is partially attenuated by the metalloprotease inhibitor, GM6001, consistent with a model in which MeHg promotes activation of ADAM metalloproteases. Finally, we demonstrate that inorganic HgCl(2) is significantly less active in inducing Notch activity, suggesting a mechanism specific to organic species of mercury. Overall, these data identify Notch as a potential target for MeHg toxicity in the developing nervous system.

Animals↗
PubMed2000

Notch gene expression during pancreatic organogenesis.

Notch receptors are involved in regulating the balance between cell differentiation and stem cell proliferation during the development of numerous tissues (Artavanis-Tsakonas, S., Matsuno, K., Fortini, M. E., 1995. Notch signaling. Science 268, 225-232). Here the expression of all four vertebrate Notch genes, their ligands, and some down-stream targets is analyzed during mouse pancreatic organogenesis. Notch 1 is the first Notch gene expressed in the pancreatic epithelium, and coexpression with HES 1 suggests that the Notch 1 pathway is activated. Notch 2 expression follows later when pancreatic buds branch and is restricted to embryonic ducts, believed to be the source for endocrine and exocrine stem cells. Notch 3 and Notch 4 are expressed in pancreatic mesenchyme and later in endothelial cells. Together these descriptive data comprise a framework for understanding the cellular basis for Notch function during pancreatic development.

Animals↗
PubMed2001

Proneural enhancement by Notch overcomes Suppressor-of-Hairless repressor function in the developing Drosophila eye.

BACKGROUND: The receptor protein Notch plays a conserved role in restricting neural-fate specification during lateral inhibition. Lateral inhibition requires the Notch intracellular domain to coactivate Su(H)-mediated transcription of the Enhancer-of-split Complex. During Drosophila eye development, Notch plays an additional role in promoting neural fate independently of Su(H) and E(spl)-C, and this finding suggests an alternative mechanism of Notch signal transduction. RESULTS: We used genetic mosaics to analyze the proneural enhancement pathway. As in lateral inhibition, the metalloprotease Kuzbanian, the EGF repeat 12 region of the Notch extracellular domain, Presenilin, and the Notch intracellular domain were required. By contrast, proneural enhancement became constitutive in the absence of Su(H), and this led to premature differentiation and upregulation of the Atonal and Senseless proteins. Ectopic Notch signaling by Delta expression ahead of the morphogenetic furrow also caused premature differentiation. CONCLUSIONS: Proneural enhancement and lateral inhibition use similar ligand binding and receptor processing but differ in the nuclear role of Su(H). Prior to Notch signaling, Su(H) represses neural development directly, not indirectly through E(spl)-C. During proneural enhancement, the Notch intracellular domain overcomes the repression of neural differentiation. Later, lateral inhibition restores the repression of neural development by a different mechanism, requiring E(spl)-C transcription. Thus, Notch restricts neurogenesis temporally to a narrow time interval between two modes of repression.

Animals↗
PubMed1999

A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.

Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.

Alzheimer Disease↗