Talk:Developmental Signals - Notch

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Cite this page: Hill, M.A. (2021, November 30) Embryology Developmental Signals - Notch. Retrieved from


Menchero S, Rollan I, Lopez-Izquierdo A, Andreu MJ, Sainz de Aja J, Kang M, Adan J, Benedito R, Rayon T, Hadjantonakis AK & Manzanares M. (2019). Transitions in cell potency during early mouse development are driven by Notch. Elife , 8, . PMID: 30958266 DOI.

Transitions in cell potency during early mouse development are driven by Notch.

Abstract The Notch signalling pathway plays fundamental roles in diverse developmental processes in metazoans, where it is important in driving cell fate and directing differentiation of various cell types. However, we still have limited knowledge about the role of Notch in early preimplantation stages of mammalian development, or how it interacts with other signalling pathways active at these stages such as Hippo. By using genetic and pharmacological tools in vivo, together with image analysis of single embryos and pluripotent cell culture, we have found that Notch is active from the 4-cell stage. Transcriptomic analysis in single morula identified novel Notch targets, such as early naïve pluripotency markers or transcriptional repressors such as TLE4. Our results reveal a previously undescribed role for Notch in driving transitions during the gradual loss of potency that takes place in the early mouse embryo prior to the first lineage decisions. © 2019, Menchero et al. KEYWORDS: Cdx2; chromosomes; developmental biology; gene expression; morula; mouse; notch; preimplantation development; trophectoderm PMID: 30958266 PMCID: PMC6486152 DOI: 10.7554/eLife.42930


Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment

FASEB J. 2017 Oct;31(10):4347-4358. doi: 10.1096/fj.201700216RR. Epub 2017 Jun 13.

Feng S1, Shi T2, Qiu J1, Yang H1, Wu Y1, Zhou W2, Wang W3, Wu H4,5.


It is well known that Notch1 signaling plays a crucial role in embryonic neural development and adult neurogenesis. The latest evidence shows that Notch1 also plays a critical role in synaptic plasticity in mature hippocampal neurons. So far, deeper insights into the function of Notch1 signaling during the different steps of adult neurogenesis are still lacking, and the mechanisms by which Notch1 dysfunction is associated with brain disorders are also poorly understood. In the current study, we found that Notch1 was highly expressed in the adult-born immature neurons in the hippocampal dentate gyrus. Using a genetic approach to selectively ablate Notch1 signaling in late immature precursors in the postnatal hippocampus by cross-breeding doublecortin (DCX)+ neuron-specific proopiomelanocortin (POMC)-α Cre mice with floxed Notch1 mice, we demonstrated a previously unreported pivotal role of Notch1 signaling in survival and function of adult newborn neurons in the dentate gyrus. Moreover, behavioral and functional studies demonstrated that POMC-Notch1-/- mutant mice showed anxiety and depressive-like behavior with impaired synaptic transmission properties in the dentate gyrus. Finally, our mechanistic study showed significantly compromised phosphorylation of cAMP response element-binding protein (CREB) in Notch1 mutants, suggesting that the dysfunction of Notch1 mutants is associated with the disrupted pCREB signaling in postnatally generated immature neurons in the dentate gyrus.-Feng, S., Shi, T., Qiu, J., Yang, H., Wu, Y., Zhou, W., Wang, W., Wu, H. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment. KEYWORDS: adult neurogenesis; anxiety; pCREB; synaptic transmission PMID: 28611114 DOI: 10.1096/fj.201700216RR


Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning

Development. 2016 Jul 1;143(13):2305-10. doi: 10.1242/dev.134213. Epub 2016 May 25.

Hunter GL1, Hadjivasiliou Z2, Bonin H3, He L4, Perrimon N4, Charras G5, Baum B1.

Abstract Coordinating cell differentiation with cell growth and division is crucial for the successful development, homeostasis and regeneration of multicellular tissues. Here, we use bristle patterning in the fly notum as a model system to explore the regulatory and functional coupling of cell cycle progression and cell fate decision-making. The pattern of bristles and intervening epithelial cells (ECs) becomes established through Notch-mediated lateral inhibition during G2 phase of the cell cycle, as neighbouring cells physically interact with each other via lateral contacts and/or basal protrusions. Since Notch signalling controls cell division timing downstream of Cdc25, ECs in lateral contact with a Delta-expressing cell experience higher levels of Notch signalling and divide first, followed by more distant neighbours, and lastly Delta-expressing cells. Conversely, mitotic entry and cell division makes ECs refractory to lateral inhibition signalling, fixing their fate. Using a combination of experiments and computational modelling, we show that this reciprocal relationship between Notch signalling and cell cycle progression acts like a developmental clock, providing a delimited window of time during which cells decide their fate, ensuring efficient and orderly bristle patterning. © 2016. Published by The Company of Biologists Ltd. KEYWORDS: Cell cycle; G2 phase; Lateral inhibition; Notch signalling; Patterning PMID 27226324

Notch-mediated lateral inhibition regulates proneural wave propagation when combined with EGF-mediated reaction diffusion

Proc Natl Acad Sci U S A. 2016 Aug 17. pii: 201602739. [Epub ahead of print]

Sato M1, Yasugi T2, Minami Y3, Miura T4, Nagayama M5.


Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt and pepper patterns during various developmental processes. However, how Notch signaling behaves in combination with other signaling systems remains elusive. The wave of differentiation in the Drosophila visual center or "proneural wave" accompanies Notch activity that is propagated without the formation of a salt and pepper pattern, implying that Notch does not form a feedback loop of lateral inhibition during this process. However, mathematical modeling and genetic analysis clearly showed that Notch-mediated lateral inhibition is implemented within the proneural wave. Because partial reduction in EGF signaling causes the formation of the salt and pepper pattern, it is most likely that EGF diffusion cancels salt and pepper pattern formation in silico and in vivo. Moreover, the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a function of Notch signaling that regulates propagation of the wave of differentiation. KEYWORDS: EGF; Notch; lateral inhibition; proneural wave; reaction diffusion

PMID 27535937


The role of epigenetic mechanisms in notch signaling during development

J Cell Physiol. 2015 May;230(5):969-81. doi: 10.1002/jcp.24851.

Schwanbeck R1.

Abstract The Notch pathway is a highly conserved cell-cell communication pathway in metazoan involved in numerous processes during embryogenesis, development, and adult organisms. Ligand-receptor interaction of Notch components on adjacent cells facilitates controlled sequential proteolytic cleavage resulting in the nuclear translocation of the intracellular domain of Notch (NICD). There it binds to the Notch effector protein RBP-J, displaces a corepressor complex and enables the induction of target genes by recruitment of coactivators in a cell-context dependent manner. Both, the gene-specific repression and the context dependent activation require an intense communication with the underlying chromatin of the regulatory regions. Since the epigenetic landscape determines the function of the genome, processes like cell fate decision, differentiation, and self-renewal depend on chromatin structure and its remodeling during development. In this review, structural features enabling the Notch pathway to read these epigenetic marks by proteins interacting with RBP-J/Notch will be discussed. Furthermore, mechanisms of the Notch pathway to write and erase chromatin marks like histone acetylation and methylation are depicted as well as ATP-dependent chromatin remodeling during the activation of target genes. An additional fine-tuning of transcriptional regulation upon Notch activation seems to be controlled by the commitment of miRNAs. Since cells within an organism have to react to environmental changes, and developmental and differentiation cues in a proper manner, different signaling pathways have to crosstalk to each other. The chromatin status may represent one major platform to integrate these different pathways including the canonical Notch signaling. J. Cell. Physiol. 230: 969-981, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company. © 2014 Wiley Periodicals, Inc. PMID 25336183


From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling

Cancer Cell. 2014 Mar 17;25(3):318-334. doi: 10.1016/j.ccr.2014.02.018.

Ntziachristos P1, Lim JS2, Sage J3, Aifantis I4. Author information


Since Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive functions of Notch signaling, and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

PMID 24651013


p63 the guardian of human reproduction

Cell Cycle. 2012 Dec 15;11(24):4545-51. doi: 10.4161/cc.22819. Epub 2012 Nov 19.

Amelio I, Grespi F, Annicchiarico-Petruzzelli M, Melino G. Source Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.


p63 is a transcriptional factor implicated in cancer and development. The presence in TP63 gene of alternative promoters allows expression of one isoform containing the N-terminal transactivation domain (TA isoform) and one N-terminal truncated isoform (ΔN isoform). Complete ablation of all p63 isoforms produced mice with fatal developmental abnormalities, including lack of epidermal barrier, limbs and other epidermal appendages. Specific TAp63-null mice, although they developed normally, failed to undergo in DNA damage-induced apoptosis during primordial follicle meiotic arrest, suggesting a p63 involvement in maternal reproduction. Recent findings have elucidated the role in DNA damage response of a novel Hominidae p63 isoform, GTAp63, specifically expressed in human spermatic precursors. Thus, these findings suggest a unique strategy of p63 gene, to evolve in order to preserve the species as a guardian of reproduction. Elucidation of the biological basis of p63 function in reproduction may provide novel approaches to the control of human fertility.

PMID 23165243


Notch signaling regulates late-stage epidermal differentiation and maintains postnatal hair cycle homeostasis

PLoS One. 2011 Jan 18;6(1):e15842.

Lin HY, Kao CH, Lin KM, Kaartinen V, Yang LT. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan, Republic of China.


BACKGROUND: Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis.

METHODOLOGY AND PRINCIPAL FINDINGS: We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes.

SIGNIFICANCE: our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells.

PMID: 21267458


The role of Notch in patterning the human vertebral column

Curr Opin Genet Dev. 2009 Aug;19(4):329-37. Epub 2009 Jul 14.

Dunwoodie SL. Source Developmental Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010 Sydney, Australia. <> Abstract The components of the Notch signaling pathway and the mechanics of signal transduction have largely been established in Drosophila. Although essential for many developmental processes in invertebrates and vertebrates, this review focuses on Notch signaling in the vertebrate-specific process of somitogenesis. More specifically it describes that mutations in genes encoding Notch pathway components (DLL3, MESP2, LFNG and HES7) cause severe congenital vertebral defects in humans. Importantly, this review highlights studies demonstrating that Dll3 is unique amongst DSL ligands acting as an inhibitor and not an activator of Notch signaling.

PMID: 19608404