Comparative and evolutionary analyses reveal conservation and divergence of the notch pathway in lophotrochozoa

AbstractLophotrochozoan species exhibit wide morphological diversity; however, the molecular basis underlying this diversity remains unclear. Here, we explored the evolution of Notch pathway genes across 37 metazoan species via phylogenetic and molecular evolutionary studies with emphasis on the lophotrochozoans. We displayed the components of Notch pathway in metazoans and found that Delta and Hes/Hey-related genes, as well as their functional domains, are duplicated in lophotrochozoans. Comparative transcriptomics analyses allow us to pinpoint sequence divergence of multigene families in the Notch signalling pathway. We identified the duplication mechanism of a mollusc-specific gene, Delta2, and found it displayed complementary expression throughout development. Furthermore, we found the functional diversification not only in expanded genes in the Notch pathway (Delta and Hes/Hey-related genes), but also in evolutionary conservative genes (Notch, Presenilin, and Su(H)). Together, this comprehensive study demonstrates conservation and divergence within the Notch pathway, reveals evolutionary relationships among metazoans, and provides evidence for the occurrence of developmental diversity in lophotrochozoans, as well as a basis for future gene function studies.

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The Notch pathway helps to pattern the tips of the Drosophila tracheal branches by selecting cell fates

Development ◽

10.1242/dev.126.11.2355 ◽

1999 ◽

Vol 126 (11) ◽

pp. 2355-2364 ◽

Cited By ~ 9

Author(s):

M. Llimargas

Keyword(s):

Notch Pathway ◽

Cell Types ◽

Notch Signalling ◽

Branching Pattern ◽

Cell Fates ◽

Tracheal System ◽

Notch Signalling Pathway ◽

Tracheal Cell ◽

Mutant Phenotypes ◽

Selection Of

The Drosophila tracheal system consists of a stereotyped network of epithelial tubes formed by several tracheal cell types. By the end of embryogenesis, when the general branching pattern is established, some specialised tracheal cells then mediate branch fusion while others extend fine terminal branches. Here evidence is presented that the Notch signalling pathway acts directly in the tracheal cells to distinguish individual fates within groups of equivalent cells. Notch helps to single out those tracheal cells that mediate branch fusion by blocking their neighbours from adopting the same fate. This function of Notch would require the restricted activation of the pathway in specific cells. In addition, and probably later, Notch also acts in the selection of those tracheal cells that extend the terminal branches. Both the localised expression and the mutant phenotypes of Delta, a known ligand for Notch, suggest that Delta may activate Notch to specify cell fates at the tips of the developing tracheal branches.

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Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽

10.1242/dev.124.6.1139 ◽

1997 ◽

Vol 124 (6) ◽

pp. 1139-1148 ◽

Cited By ~ 31

Author(s):

J.L. Pompa de la ◽

A. Wakeham ◽

K.M. Correia ◽

E. Samper ◽

S. Brown ◽

...

Keyword(s):

Cell Fate ◽

Notch Pathway ◽

Stem Cell Differentiation ◽

Notch Signalling ◽

Signalling Pathway ◽

Notch Signalling Pathway ◽

Altered Expression ◽

Cell Fate Decisions ◽

Targeted Mutation ◽

Multiple Cell

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

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Overexpressing microRNA-34a overcomes ABCG2-mediated drug resistance to 5-FU in side population cells from colon cancer via suppressing DLL1

The Journal of Biochemistry ◽

10.1093/jb/mvaa012 ◽

2020 ◽

Vol 167 (6) ◽

pp. 557-564

Author(s):

Zheng-Yuan Xie ◽

Fen-Fen Wang ◽

Zhi-Hua Xiao ◽

Si-Fu Liu ◽

Sheng-Lan Tang ◽

...

Keyword(s):

Colon Cancer ◽

Drug Resistance ◽

Side Population ◽

Critical Role ◽

Notch Pathway ◽

Notch Signalling ◽

Signalling Pathway ◽

Luciferase Reporter ◽

Small Subset ◽

Notch Signalling Pathway

Abstract Colon cancer side population (SP) cells are a small subset of cancer cells that have cancer stemness capacity and enhanced drug resistance. ABCG2 is a multidrug resistance-related protein in SP cells and has been demonstrated to be regulated by Notch signalling pathway. Recently, microRNAs are reported to play a critical role in SP cell fate. However, their role in ABCG2-mediated drug resistance in colon cancer SP cells remains unclear. In the current study, the different expressions of miR-552, miR-611, miR-34a and miR-5000-3p were compared within SP and non-SP cells, which were separated from human colon cancer cell lines (SW480 and LoVo). We found that miR-34a was significantly down-regulated in SP cells and that overexpressing miR-34a overcame drug resistance to 5-fluorouracil (5-FU). The luciferase reporter assay indicated that miR-34a negatively regulated DLL1, a ligand of Notch signalling pathway, via binding with 3′-untranslated region of its messenger RNA. In addition, overexpressing miR-34a overcame ABCG2-mediated resistance to 5-FU via DLL1/Notch pathway in vitro, and suppressed tumour growth under 5-FU treatment in vivo. In conclusion, our findings suggest that miR-34a acts as a tumour suppressor via enhancing chemosensitivity to 5-FU in SP cells, which provides a novel therapeutic target in chemotherapy-resistant colon cancer.

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A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex

Development ◽

10.1242/dev.125.15.2893 ◽

1998 ◽

Vol 125 (15) ◽

pp. 2893-2900 ◽

Cited By ~ 7

Author(s):

P. Ligoxygakis ◽

S.Y. Yu ◽

C. Delidakis ◽

N.E. Baker

Keyword(s):

Cell Fate ◽

Notch Pathway ◽

Signal Transduction Pathway ◽

Notch Signalling ◽

Transduction Pathway ◽

Notch Signalling Pathway ◽

Bhlh Genes ◽

Drosophila Eye ◽

Enhancer Of Split ◽

Signalling Process

The Notch signalling pathway is involved in many processes where cell fate is decided. Previous work showed that Notch is required at successive steps during R8 specification in the Drosophila eye. Initially, Notch enhances atonal expression and promotes atonal function. After atonal autoregulation has been established, Notch signalling represses atonal expression during lateral specification. In this paper we investigate which known components of the Notch pathway are involved in each signalling process. Using clonal analysis we show that a ligand of Notch, Delta, is required along with Notch for both proneural enhancement and lateral specification, while the downstream components Suppressor-of-Hairless and Enhancer-of-Split are involved only in lateral specification. Our data point to a distinct signal transduction pathway during proneural enhancement by Notch. Using misexpression experiments we also show that particular Enhancer-of-split bHLH genes can differ greatly in their contribution to lateral specification.

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The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

PLoS Biology ◽

10.1371/journal.pbio.3001334 ◽

2021 ◽

Vol 19 (7) ◽

pp. e3001334

Author(s):

Miren Maicas ◽

Ángela Jimeno-Martín ◽

Andrea Millán-Trejo ◽

Mark J. Alkema ◽

Nuria Flames

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Target Genes ◽

Cell Signalling ◽

Notch Pathway ◽

Receptor Activation ◽

Notch Signalling ◽

Notch Receptor ◽

Specific Gene ◽

Effector Genes

During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling.

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Delta 1-activated notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis

Development ◽

10.1242/dev.127.23.5213 ◽

2000 ◽

Vol 127 (23) ◽

pp. 5213-5224 ◽

Cited By ~ 6

Author(s):

M. Delfini ◽

E. Hirsinger ◽

O. Pourquie ◽

D. Duprez

Keyword(s):

Limb Development ◽

Notch Pathway ◽

Muscle Differentiation ◽

Notch Signalling ◽

Limb Bud ◽

Specific Gene ◽

Expression Domain ◽

Helix Loop Helix ◽

The Right

The myogenic basic helix-loop-helix (bHLH) transcription factors, Myf5, MyoD, myogenin and MRF4, are unique in their ability to direct a program of specific gene transcription leading to skeletal muscle phenotype. The observation that Myf5 and MyoD can force myogenic conversion in non-muscle cells in vitro does not imply that they are equivalent. In this paper, we show that Myf5 transcripts are detected before those of MyoD during chick limb development. The Myf5 expression domain resembles that of Pax3 and is larger than that of MyoD. Moreover, Myf5 and Pax3 expression is correlated with myoblast proliferation, while MyoD is detected in post-mitotic myoblasts. These data indicate that Myf5 and MyoD are involved in different steps during chick limb bud myogenesis, Myf5 acting upstream of MyoD. The progression of myoblasts through the differentiation steps must be carefully controlled to ensure myogenesis at the right place and time during wing development. Because Notch signalling is known to prevent differentiation in different systems and species, we sought to determine whether these molecules regulate the steps occurring during chick limb myogenesis. Notch1 transcripts are associated with immature myoblasts, while cells expressing the ligands Delta1 and Serrate2 are more advanced in myogenesis. Misexpression of Delta1 using a replication-competent retrovirus activates the Notch pathway. After activation of this pathway, myoblasts still express Myf5 and Pax3 but have downregulated MyoD, resulting in inhibition of terminal muscle differentiation. We conclude that activation of Notch signalling during chick limb myogenesis prevents Myf5-expressing myoblasts from progressing to the MyoD-expressing stage.

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Notch pathway: a bistable inducer of biological noise?

Cell Communication and Signaling ◽

10.1186/s12964-019-0453-0 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 3

Author(s):

Filip Vujovic ◽

Neil Hunter ◽

Ramin M. Farahani

Keyword(s):

Alternative Hypothesis ◽

Notch Pathway ◽

Notch Signalling ◽

Signalling Pathway ◽

Biological Noise ◽

Notch Signalling Pathway ◽

Binary Output ◽

Lineage Differentiation

Abstract Notch signalling pathway is central to development of metazoans. The pathway codes a binary fate switch. Upon activation, downstream signals contribute to resolution of fate dichotomies such as proliferation/differentiation or sub-lineage differentiation outcome. There is, however, an interesting paradox in the Notch signalling pathway. Despite remarkable predictability of fate outcomes instructed by the Notch pathway, the associated transcriptome is versatile and plastic. This inconsistency suggests the presence of an interface that compiles input from the plastic transcriptome of the Notch pathway but communicates only a binary output in biological decisions. Herein, we address the interface that determines fate outcomes. We provide an alternative hypothesis for the Notch pathway as a biological master switch that operates by induction of genetic noise and bistability in order to facilitate resolution of dichotomous fate outcomes in development. Graphical abstract

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Ligand-receptor interactions and trans-endocytosis of Delta, Serrate and Notch: members of the Notch signalling pathway in Drosophila

Journal of Cell Science ◽

10.1242/jcs.112.19.3289 ◽

1999 ◽

Vol 112 (19) ◽

pp. 3289-3297 ◽

Cited By ~ 14

Author(s):

K.M. Klueg ◽

M.A. Muskavitch

Keyword(s):

Cultured Cells ◽

Notch Pathway ◽

Notch Signalling ◽

Molecular Evidence ◽

Cell Surfaces ◽

Aggregation Assay ◽

Notch Signalling Pathway ◽

Receptor Interactions ◽

Heterotypic Interactions ◽

Homotypic Interactions

Molecular evidence has established that direct heterotypic interactions occur between the Drosophila receptor Notch and the ligands Delta and Serrate, and that homotypic interactions occur between Delta molecules on opposing cell surfaces. Using an aggregation assay developed for Drosophila cultured cells, we have compared the affinities of these interactions. We find that the heterotypic interactions between Notch and the ligands Delta and Serrate have higher affinities than homotypic interactions between Delta molecules. Contrary to previous suggestions, our evidence implies that the interactions between Serrate and Notch are similar in affinity to those between Delta and Notch. We find that Fringe does not detectably affect the ligand-receptor interactions of the Notch pathway in cultured cells. Furthermore, we find that Serrate, like Delta, is a transmembrane ligand that can participate in reciprocal trans-endocytosis of ligand and receptor between expressing cells. Our findings imply that qualitative differences between Delta- and Serrate-mediated Notch signalling depend on characteristics other than intrinsic ligand-receptor affinities or the ability to participate in reciprocal ligand and receptor trans-endocytosis.

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The role of presenilin 1 during somite segmentation

Development ◽

10.1242/dev.128.8.1391 ◽

2001 ◽

Vol 128 (8) ◽

pp. 1391-1402 ◽

Cited By ~ 1

Author(s):

K.i. Koizumi ◽

M. Nakajima ◽

S. Yuasa ◽

Y. Saga ◽

T. Sakai ◽

...

Keyword(s):

Notch Pathway ◽

Notch Signalling ◽

Signalling Pathway ◽

Paraxial Mesoderm ◽

Presenilin 1 ◽

Wild Type ◽

Presomitic Mesoderm ◽

Notch Signalling Pathway ◽

Deficient Mice

The Notch signalling pathway plays essential roles during the specification of the rostral and caudal somite halves and subsequent segmentation of the paraxial mesoderm. We have re-investigated the role of presenilin 1 (Ps1; encoded by Psen1) during segmentation using newly generated alleles of the Psen1 mutation. In Psen1-deficient mice, proteolytic activation of Notch1 was significantly affected and the expression of several genes involved in the Notch signalling pathway was altered, including Δ-like3, Hes5, lunatic fringe (Lfng) and Mesp2. Thus, Ps1-dependent activation of the Notch pathway is essential for caudal half somite development. We observed defects in Notch signalling in both the caudal and rostral region of the presomitic mesoderm. In the caudal presomitic mesoderm, Ps1 was involved in maintaining the amplitude of cyclic activation of the Notch pathway, as represented by significant reduction of Lfng expression in Psen1-deficient mice. In the rostral presomitic mesoderm, rapid downregulation of the Mesp2 expression in the presumptive caudal half somite depends on Ps1 and is a prerequisite for caudal somite half specification. Chimaera analysis between Psen1-deficient and wild-type cells revealed that condensation of the wild-type cells in the caudal half somite was concordant with the formation of segment boundaries, while mutant and wild-type cells intermingled in the presomitic mesoderm. This implies that periodic activation of the Notch pathway in the presomitic mesoderm is still latent to segregate the presumptive rostral and caudal somite. A transient episode of Mesp2 expression might be needed for Notch activation by Ps1 to confer rostral or caudal properties. In summary, we propose that Ps1 is involved in the functional manifestation of the segmentation clock in the presomitic mesoderm.

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Post-transcriptional regulation in Xenopus embryos: role and targets of EDEN-BP

Biochemical Society Transactions ◽

10.1042/bst0331541 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1541-1543 ◽

Cited By ~ 7

Author(s):

H.B. Osborne ◽

C. Gautier-Courteille ◽

A. Graindorge ◽

C. Barreau ◽

Y. Audic ◽

...

Keyword(s):

Transcriptional Regulation ◽

Xenopus Laevis ◽

Microarray Analysis ◽

Notch Pathway ◽

Notch Signalling ◽

Regulatory Process ◽

Signalling Pathway ◽

Notch Signalling Pathway ◽

Early Embryos ◽

Post Transcriptional Regulation

EDEN (embryo deadenylation element)-dependent deadenylation is a regulatory process that was initially identified in Xenopus laevis early embryos and was subsequently shown to exist in Drosophila oocytes. Recent data showed that this regulatory process is required for somitic segmentation in Xenopus. Inactivation of EDEN-BP (EDEN-binding protein) causes severe segmentation defects, and the expression of segmentation markers in the Notch signalling pathway is disrupted. We showed that the mRNA encoding XSu(H) (Xenopus suppressor of hairless), a protein central to the Notch pathway, is regulated by EDEN-BP. Our data also indicate that other segmentation RNAs are targets for EDEN-BP. To identify new EDEN-BP targets, a microarray analysis has been undertaken.

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