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PubMed2004

Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.

During normal development Notch receptor signaling is important in regulating numerous cell fate decisions. Mutations that truncate the extracellular domain of Notch receptors can cause aberrant signaling and promote unregulated cell growth. We have examined two types of truncated Notch oncoproteins that arise from proviral insertion into the Notch4 gene (Notch4/int-3) or a chromosomal translocation involving the Notch1 gene (TAN-1). Both Notch4/int-3 and TAN-1 oncoproteins lack most or all of their ectodomain. Normal Notch signaling requires gamma-secretase/presenilin-mediated proteolytic processing, but whether Notch oncoproteins are also dependent on gamma-secretase/presenilin activity is not known. We demonstrate that Notch4/int-3-induced activation of the downstream transcription factor, CSL, is abrogated in cells deficient in presenilins or treated with a pharmacological inhibitor of gamma-secretase/presenilins. Furthermore, we find that both Notch4/int-3 and TAN-1 accumulate at the cell surface, where presenilin-dependent cleavage occurs, when gamma-secretase/presenilin activity is inhibited. gamma-Secretase/presenilin inhibition effectively blocks cellular responses to Notch4/int-3, but not TAN-1, apparently because some TAN-1 polypeptides lack transmembrane domains and do not require gamma-secretase/presenilin activity for nuclear access. These studies highlight potential uses and limitations of gamma-secretase/presenilin inhibitors in targeted therapy of Notch-related neoplasms.

Adenoviridae↗

PubMed2004

Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.

INTRODUCTION: Notch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors. METHODS: In order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists. RESULTS: Utilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells. CONCLUSION: These studies suggest that Notch signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Based on these findings we propose that abnormal Notch signaling may contribute to mammary carcinogenesis by deregulating the self-renewal of normal mammary stem cells.

Cell Differentiation↗

PubMed2004

Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation.

Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation. In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (alpha-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development.

Actins↗

PubMed1998

Distinct expression patterns of notch family receptors and ligands during development of the mammalian inner ear.

The cochlea and vestibular structures of the inner ear labyrinth develop from the otic capsule via step-wise regional and cell fate specification. Each inner ear structure contains a sensory epithelium, composed of hair cells, the mechanosensory transducers, and supporting cells. We examined the spatio-temporal expression of genes in the Notch signaling pathway, Notch receptors (Notch1-4) and two ligands, Jagged1 and Delta1, in the developing mammalian inner ear. Our results show that Notch1 and Jagged1 are first expressed in the otic vesicle, likely involved in differentiation of the VIIIth nerve ganglion neurons, and subsequently within the inner ear sensory epithelia, temporally coincident with initial hair cell differentiation. Notch1 expression is specific to hair cells and Jagged1 to supporting cells. Their expression persists into adult. Notch2, Notch3, Notch4, and Delta1 are excluded from the inner ear epithelia. These data support the hypothesis that Notch signaling is involved in hair cell differentiation during inner ear morphogenesis.

Animals↗

PubMed2000

Ras pathway signals are required for notch-mediated oncogenesis.

The Notch genes of C. elegans, Drosophila melanogaster and vertebrates encode receptors responsible for cell fate decisions during development. These Notch receptors and their ligands, Delta and Jagged, have been implicated in several human diseases. Truncated, constitutively active mutant forms of the Notch receptor appear to be involved in human T-cell leukemia, mammary carcinomas in mice, and a tumorous germline phenotype in C. elegans. Since activated Notch induces solitary tumors in transgenic mice, it is highly likely that collaborating genetic events are required for tumor formation. We have assessed four signal transduction pathways to determine which might play additional roles in malignant transformation in concert with activated Notch4. Our results suggest that transformation by Notch does not, as might have been expected, depend on the Src-like kinases Lck and Fyn, nor upon signals from protein kinase A and C (PKA, PKC). Rather, transformation by Notch requires active signals from the Erk/MAP kinase and PI-3 kinase pathways downstream of Ras. Oncogene (2000) 19, 4191 - 4198

Animals↗

PubMed2003

Notch signaling in primary endothelial cells.

The Notch family of cell-surface receptors has been proposed to regulate cell-fate decisions by modulating the ability of each cell to respond to environmental cues. In vertebrates, gain-of-function and loss-of-function studies have demonstrated a requirement for Notch signaling for proper patterning of the vasculature during embryogenesis. To examine the molecular mechanisms by which Notch regulates vascular development, we analyzed changes in gene expression in response to Notch signaling. Notch signal transduction and function were assessed in primary human endothelial cells isolated from the dermal microvasculature of neonates, HMVECd. We demonstrate that HMVECd cells express a heterodimeric form of endogenous Notch4 on their cell surface. Using an in vitro coculture assay, we found that Delta4 can function as a ligand for Notch4 in HMVECd cells. Moreover, ectopic expression of an activated allele of Notch4 upregulated the expression of Delta4, suggesting that there may be a regulatory loop between Notch4 and its ligand, Delta4. Notch4 activation also induced the expression of the transcriptional repressors, HES1, HERP1, and HERP2, as well as ephrinB2, an angiogenic factor proposed to be involved in arterial/venous endothelial cell specification.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation.

Notch signaling functions to regulate cell-fate decisions by modulating differentiation, proliferation, and survival of cells. Notch receptors and ligands are expressed in embryonic vasculature and are required for the remodeling of the primary embryonic vasculature of mice. Here, we characterize the expression patterns of Notch1, Notch4, and Jagged1 proteins during the process of folliculogenesis and corpus luteum formation in the mouse ovary, an organ with dynamic physiological angiogenic growth. These Notch proteins and ligand are expressed in a subset of ovarian vessels, including both mature ovarian vasculature as well as angiogenic neovessels. Their expression in the ovary was found in both endothelial and vascular associated mural cells. Our data suggest a complex regulatory role for the Notch signaling pathway during mouse oogenesis and ovarian neovascularization.

Animals↗

PubMed2003

Two NOTCH4 polymorphisms and their relation to schizophrenia susceptibility and different personality traits.

BACKGROUND: Recently, linkage disequilibrium mapping of the major histocompatibility complex region on the short arm of human chromosome 6 suggested that the NOTCH4 locus is highly associated with schizophrenia. OBJECTIVES AND METHODS: We analysed two polymorphisms in this gene in Swedish schizophrenic patients ( =74) and control subjects ( =135). The NOTCH4 variants were also analysed in schizophrenic patients with regard to subdiagnosis, age at first hospitalization, abuse/dependence of alcohol, solvents, or drugs, previous suicide attempts, extrapyramidal symptoms, treatment with anticholinergic drugs, and response to anti-psychotic drug treatment. Control subjects were scrutinized with regard to personality, another partially heritable trait suggested being of importance in schizophrenia. In addition, two intermediate endophenotypes suggested being of importance in schizophrenia, dopamine D(2) receptor density in striatum and monoamine metabolites in cerebrospinal fluid, respectively, were investigated with regard to the two NOTCH4 variants. RESULTS: There was no significant association between the patients and the controls for the two investigated polymorphisms neither for the parameters analysed in the schizophrenia material. The NOTCH4 SNP2 variant, an A-->G substitution, was associated with the Karolinska Scales of Personality Irritability scale. The NOTCH4 (CTG)(n) variant was associated with the revised NEO personality inventory Extraversion and Activity (E4) scales. However, after correction for multiple testing, no difference remained significant. The results for the endophenotypes and the polymorphisms were non-significant. CONCLUSIONS: The present study does not support that the investigated NOTCH4 variants have a major influence on susceptibility to schizophrenia or related neurobiological traits.

Biogenic Monoamines↗

PubMed2006

Critical role of endothelial Notch1 signaling in postnatal angiogenesis.

Notch receptors are important mediators of cell fate during embryogenesis, but their role in adult physiology, particularly in postnatal angiogenesis, remains unknown. Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow recovery and postnatal neovascularization in response to hindlimb ischemia in haploinsufficient global or endothelial-specific Notch1(+/-) mice, but not Notch4(-/-) mice, were impaired compared with wild-type mice. The expression of vascular endothelial growth factor (VEGF) in response to ischemia was comparable between wild-type and Notch mutant mice, suggesting that Notch1 is downstream of VEGF signaling. Treatment of endothelial cells with VEGF increases presenilin proteolytic processing, gamma-secretase activity, Notch1 cleavage, and Hes-1 (hairy enhancer of split homolog-1) expression, all of which were blocked by treating endothelial cells with inhibitors of phosphatidylinositol 3-kinase/protein kinase Akt or infecting endothelial cells with a dominant-negative Akt mutant. Indeed, inhibition of gamma-secretase activity leads to decreased angiogenesis and inhibits VEGF-induced endothelial cell proliferation, migration, and survival. Overexpression of the active Notch1 intercellular domain rescued the inhibitory effects of gamma-secretase inhibitors on VEGF-induced angiogenesis. These findings indicate that the phosphatidylinositol 3-kinase/Akt pathway mediates gamma-secretase and Notch1 activation by VEGF and that Notch1 is critical for VEGF-induced postnatal angiogenesis. These results suggest that Notch1 may be a novel therapeutic target for improving angiogenic response and blood flow recovery in ischemic limbs.

Amyloid Precursor Protein Secretases↗

PubMed2004

Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-Jkappa.

Notch proteins comprise a family of transmembrane receptors. Ligand activation of Notch releases the intracellular domain of the receptor that translocates to the nucleus and regulates transcription through the DNA-binding protein RBP-Jkappa. Previously, it has been shown that the Notch4 intracellular region (N4IC) can inhibit endothelial sprouting and angiogenesis. Here, N4IC deletion mutants were assessed for their ability to inhibit human microvascular endothelial cell (HMEC) sprouting with the use of a quantitative endothelial sprouting assay. Deletion of the ankyrin repeats, but not the RAM (RBP-Jkappa associated module) domain or C-terminal region (CT), abrogated the inhibition of fibroblast growth factor 2 (FGF-2)- and vascular endothelial growth factor (VEGF)-induced sprouting by Notch4, whereas the ankyrin repeats alone partially blocked sprouting. The ankyrin repeats were also the only domain required for up-regulation of RBP-Jkappa-dependent gene expression. Interestingly, enforced expression of the ankyrin domain alone was sufficient to up-regulate some, but not all, RBP-Jkappa-dependent genes. Although N4IC reduced VEGF receptor-2 (VEGFR-2) and vascular endothelial (VE)-cadherin expression, neither of these events is necessary and sufficient to explain N4IC-mediated inhibition of sprouting. A constitutively active RBP-Jkappa mutant significantly inhibited HMEC sprouting but not as strongly as N4IC. Thus, Notch4-induced inhibition of sprouting requires the ankyrin repeats and appears to involve RBP-Jkappa-dependent and -independent signaling.

Ankyrin Repeat↗

PubMed2005

Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: a novel syndrome.

BACKGROUND: Autosomal-dominant forms of hematuria have been mostly related to mutations in the COL4A3/COL4A4 genes. Patients with thin basement membrane (BM) disease do not have extrarenal manifestations, while those with Alport syndrome often present with hearing loss, anterior lenticonus, and dot-and-fleck retinopathy. METHODS: We performed a phenotypic study and a candidate gene approach in a four-generation family presenting with autosomal-dominant hematuria associated with extrarenal manifestations. Renal biopsy was analyzed for determination of BM thickness and expression of chains of type IV collagen. Linkage to 18 candidate genes/loci was investigated using polymorphic microsatellite markers. RESULTS: In all affected patients, hematuria without proteinuria was associated with muscular contractures and retinal arterial tortuosities responsible for retinal hemorrhages. Cardiac arrhythmia, Raynaud phenomena, and brain MRI abnormalities were also observed. Despite the presence of red cells in tubule sections, no glomerular abnormalities were found by electron microscopy. Expression of type IV collagen chains and glomerular BM thickness was normal. We searched for a molecular defect affecting either BM or angiogenesis. Linkage analyses of genes encoding BM components (COL4A3/COL4A4, COL6A1, COL6A2, COL6A3, FBLN1), and angiogenic factors or their receptors (VHL, ANPT1, ANPT2, TIE, TEK, NOTCH2, NOTCH3, NOTCH4, DLL4, JAG1, JAG2) and of the facio-sapulo-humeral dystrophy and 3q21 loci failed to show segregation of the disease with those gene loci. CONCLUSION: We have identified a new inherited hematuria syndrome associated with retinal vessel tortuosities and contractures. We recommend performing a fundus examination in patients with familial hematuria and episodes of visual impairment, as well as a urinary analysis in patients with retinal arterial tortuosity or congenital muscular contractures.

Collagen Type IV↗

PubMed2005

The role of notch in modeling and maintaining the vasculature.

The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate, and are comprised of 4 members in mammals (Notch1 to Notch4). Following intra cellular processing of the full-length protein, Notch is expressed at the cell surface as a heterodimeric receptor. Engagement by ligand results in a 2-step cleavage of the Notch heterodimer, releasing the intracellular domain of Notch and allowing translocation to the nucleus. The intracellular domain of Notch interacts with the DNA-binding factor, CSL, resulting in transactivation at various promoters, in particular those of various basic helix-loop-helix factors of the HES (Hairy and Enhancer of Split) and HRT families (Hairy-Related Transcription factor). Recent findings implicate Notch as playing a critical and non-redundant role in vascular development and maintenance. This article briefly reviews vessel development and Notch signaling and highlights studies that examine Notch functions such as proliferation, cell survival, migration, adhesion, and mesenchymal transformation in the vasculature. Human diseases caused by Notch pathway members are also discussed.

Animals↗

PubMed2006

Notch1-induced transformation of RKE-1 cells requires up-regulation of cyclin D1.

RKE-1 cells induced to overexpress activated Notch1 (RKE-ER-N(ic)) exhibit increased cyclin D1 transcripts and become transformed. However, the oncogenic pathway of Notch1-induced transformation is not known. Here, we use mutational analysis to functionally identify the sole region of the cyclin D1 promoter that responds to activated Notch1. The same region responds to activated Notch4 as well as to physiologic Notch ligand-induced Notch receptor signaling. The cyclin D1 gene was subsequently found to be a physiologic target of Notch signaling in Pofut1(-/-) mouse embryos defective in canonical Notch signaling and in embryos with an inactivating mutation in Notch1. To determine if Notch1-induced cyclin D1 expression in RKE-ER-N(ic) cells plays a direct role in transformation, cyclin D1 up-regulation was inhibited using a cyclin D1 antisense cDNA. We report here that transformation of RKE-ER-N(ic) cells is dependent on increased expression of cyclin D1 protein, which represents a new mechanism of Notch1-induced transformation.

Animals↗

PubMed2005

Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis.

BACKGROUND: The interaction of Notch receptors with their transmembrane ligands Delta and Jagged plays an important role not only in the organization of a variety of tissues but also in several genetic disorders and cancer development. The functional involvement of the Notch signaling in rheumatoid arthritis (RA) has been reported previously, but the expression profile of Notch-related molecules, as well as their relation with clinicopathological parameters, remains unclear. METHODS: In this study, we analyzed the immunohistochemical staining pattern of four Notch receptors (Notch1-4) and their ligands (Delta1 and Jagged1) in 14 synovial tissues obtained from 14 RA patients. RESULTS: Notch2 and Notch4 were expressed in limited areas in a few samples or in small blood vessels, respectively. Notch1, Notch3, Delta1, and Jagged1 were overexpressed in the synovial lining and sublining cells on synovial hyperplastic lesions in all samples. Notch1 expression was also observed in T and B lymphocytes of lymphoid follicles independently. Notch1 and Notch3 expression overlapped with that of Jagged1, as determined by confocal microscopy. Activation of Notch1 signaling in the RA synovium was identified using a specific antibody to the cleaved form of Notch1. The expression of these molecules did not show any correlation with clinicopathological parameters. CONCLUSIONS: Our results suggest that Notch signaling is activated in RA synovium but does not necessarily reflect the pathological condition of RA.

Adolescent↗

PubMed2001

SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.

Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40 repeats. In the case of Notch1, this block leads to an increase in Notch signaling stimulated by either an activated form of the Notch1 receptor or Jagged1-induced signaling through Notch1. Expression of dominant-negative SEL-10 leads to stabilization of the intracellular domain of Notch1. The Notch4 intracellular domain bound to SEL-10, but its activity was not increased as a result of dominant-negative SEL-10 expression. SEL-10 bound Notch4 via the WD40 repeats and bound preferentially to a phosphorylated form of Notch4 in cells. We mapped the region of Notch4 essential for SEL-10 binding to the C-terminal region downstream of the ankyrin repeats. When this C-terminal fragment of Notch4 was expressed in cells, it was highly labile but could be stabilized by the expression of dominant-negative SEL-10. Ubiquitination of Notch1 and Notch4 intracellular domains in vitro was dependent on SEL-10. Although SEL-10 interacts with the intracellular domains of both Notch1 and Notch4, these proteins respond differently to interference with SEL-10 function. Thus, SEL-10 functions to promote the ubiquitination of Notch proteins; however, the fates of these proteins may differ.

Animals↗

PubMed2001

Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels.

Mice with targeted mutations in genes required for Notch signal transduction die during embryogenesis, displaying overt signs of hemorrhage due to defects in their vascular development. Surprisingly, directed expression of a constitutively active form of Notch4 within mouse endothelial cells produces a similar vascular embryonic lethality. Moreover, patients with mutations in Notch3 exhibit the cerebral vascular disorder, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These findings underscore the importance of Notch signaling in vascular development; however, they do not identify the specific functional defect. Here, we report that Notch1, Notch3, Notch4, Delta4, Jagged1 and Jagged2 are all expressed in arteries, but are not expressed by veins. These findings identify an aspect of Notch signaling that could contribute to the mechanism by which this pathway modulates vascular morphogenesis.

Animals↗

PubMed2006

A novel mechanism of transcriptional repression of p27kip1 through Notch/HRT2 signaling in vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) proliferation occurs in vascular obstructive events such as atherosclerosis and restenosis. We previously showed that Notch receptors are induced in smooth muscle cells during vascular remodeling. Our goal was to determine the mechanisms employed by Notch signaling to regulate proliferation. Activation of Notch1 and Notch4 induced the VSMC-selective target genes HRT1 and HRT2, promoted cell cycle transit in smooth muscle cells, and led to loss of density-dependent growth inhibition. This was associated with a reduction in levels of the cyclin-dependent kinase inhibitor (cdk) p27(kip1). Over-expression of p27(kip1) resulted in a dose-dependent rescue of the Notch-induced phenotype and exit from the cell cycle. In addition, HRT2 expression was sufficient to promote S-phase entry, and we demonstrate that HRT2 interacts directly with the p27(kip1) promoter to repress transcription. Transcriptional repression occurred within the approximately 774 bp minimal p27(kip1) promoter region and mutational analysis demonstrated that repression is largely dependent on a conserved class-C domain. Our data show that Notch signaling acts to promote a proliferative phenotype in VSMC by modulation of the G1/S-phase checkpoint. In addition, we define a novel mechanism by which the Notch effector, HRT2, interacts directly with the class-C domain of the p27(kip1) promoter, repressing its expression. These studies identify a novel transcriptional target of HRT2, and show that Notch effectors directly control cell cycle regulatory components. We suggest that this mechanism is relevant to hyperproliferative states in VSMC seen during vascular remodeling and repair.

Adenoviridae↗

PubMed2004

Math1 controls cerebellar granule cell differentiation by regulating multiple components of the Notch signaling pathway.

Cerebellar granule cells (CGC) are the most abundant neurons in the mammalian brain, and an important tool for unraveling molecular mechanisms underlying neurogenesis. Math1 is a bHLH transcription activator that is essential for the genesis of CGC. To delineate the effects of Math1 on CGC differentiation, we generated and studied primary cultures of CGC progenitors from Math1/lacZ knockout mice. Rhombic lip precursors appeared properly positioned, expressed CGC-specific markers, and maintained Math1 promoter activity in vivo and in vitro, suggesting that Math1 is not essential for the initial stages of specification or survival of CGC. Moreover, the continuous activity of Math1 promoter in the absence of MATH1, indicated that MATH1 was not necessary for the activation of its own expression. After 6, but not 3, days in culture, Math1 promoter activity was downregulated in control cultures, but not in cells from Math1 null mice, thus implying that Math1 participates in a negative regulatory feedback loop that is dependent on increased levels of MATH1 generated through the positive autoregulatory feedback loop. In addition, Math1 null CGC did not differentiate properly in culture, and were unable to extend processes. All Notch signaling pathway receptors and ligands tested were expressed in the rhombic lip at embryonic date 14, with highest levels of Notch2 and Jag1. However, Math1-null rhombic lip cells presented conspicuous downregulation of Notch4 and Dll1. Moreover, of the two transcriptional repressors known to antagonize Math1, Hes5 (but not Hes1) was downregulated in Math1-null rhombic lip tissue and primary cultures, and was shown to bind MATH1, thus revealing a negative regulatory feedback loop. Taken together, our data demonstrate that CGC differentiation, but not specification, depends on Math1, which acts by regulating the level of multiple components of the Notch signaling pathway.

Animals↗