Developmental Signals - Notch

Embryology - 2 Dec 2023        Expand to Translate
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Introduction

Notch structure cartoon

The notch proteins were first identified in drosophila development and have since been identified as regulators of cell fate decisions during development. These are a family of cell surface transmembrane receptors that pass once through the plasma membrane.

This signalling pathway is involved with many different developmental patterning pathways and in the adult is a key regulator in the vascular system.

Notch Links: Notch structure cartoon | Notch signaling pathway cartoon | Notch and signaling pathway cartoon | Developmental Signals - Notch | Molecular Factors

Some Recent Findings

Mouse somitogenesis genes

Transitions in cell potency during early mouse development are driven by Notch "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." Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning "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." Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors "Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection." Respiratory System Development

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Notch

Older papers

These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. Notch regulation of myogenic versus endothelial fates of cells that migrate from the somite to the limb "Multipotent Pax3-positive (Pax3(+)) cells in the somites give rise to skeletal muscle and to cells of the vasculature. We had previously proposed that this cell-fate choice depends on the equilibrium between Pax3 and Foxc2 expression. In this study, we report that the Notch pathway promotes vascular versus skeletal muscle cell fates. ...We now demonstrate that in addition to the inhibitory role of Notch signaling on skeletal muscle cell differentiation, the Notch pathway affects the Pax3:Foxc2 balance and promotes the endothelial versus myogenic cell fate, before migration to the limb, in multipotent Pax3(+) cells in the somite of the mouse embryo." Limb Development | Muscle Development The precise timeline of transcriptional regulation reveals causation in mouse somitogenesis network "In vertebrate development, the segmental pattern of the body axis is established as somites, masses of mesoderm distributed along the two sides of the neural tube, are formed sequentially in the anterior-posterior axis. This mechanism depends on waves of gene expression associated with the Notch, Fgf and Wnt pathways." Role of p63 and the Notch pathway in cochlea development and sensorineural deafness "The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. ...these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations." Sensory - Hearing and Balance Development Notch signaling regulates late-stage epidermal differentiation and maintains postnatal hair cycle homeostasis "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. ...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." Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development "The role of Notch signaling in cartilage differentiation and maturation in vivo was examined. Conditional Notch pathway gain and loss of function was achieved using a Cre/loxP approach to manipulate Notch signaling in cartilage precursors and chondrocytes of the developing mouse embryo. Conditional overexpression of activated Notch intracellular domain (NICD) in the chondrocyte lineage results in skeletal malformations with decreased cartilage precursor proliferation and inhibited hypertrophic chondrocyte differentiation. Likewise, expression of NICD in cartilage precursors inhibits sclerotome differentiation, resulting in severe axial skeleton abnormalities. Furthermore, conditional loss of Notch signaling via RBP-J gene deletion in the chondrocyte lineage results in increased chondrocyte proliferation and skeletal malformations consistent with the observed increase in hypertrophic chondrocytes. In addition, the Notch pathway inhibits expression of Sox9 and its target genes required for normal chondrogenic cell proliferation and differentiation. Together, our results demonstrate that appropriate Notch pathway signaling is essential for proper chondrocyte progenitor proliferation and for the normal progression of hypertrophic chondrocyte differentiation into bone in the developing appendicular and axial skeletal elements." Cartilage Development Notch signalling in the paraxial mesoderm is most sensitive to reduced Pofut1 levels during early mouse development "Notch-dependent processes apparently differ with respect to their requirement for levels of POFUT1. Normal Lfng expression and anterior-posterior somite patterning is highly sensitive to reduced POFUT1 levels in early mammalian embryos, whereas other early Notch-dependent processes such as establishment of left-right asymmetry or neurogenesis are not. Thus, it appears that in the presomitic mesoderm (PSM) Notch signalling is particularly sensitive to POFUT1 levels. Reduced POFUT1 levels might affect Notch trafficking or overall O-fucosylation. Alternatively, reduced O-fucosylation might preferentially affect sites that are substrates for LFNG and thus important for somite formation and patterning."

Notch Signaling

Notch signaling pathway

Secretory pathway - modifications during the secretion of Notch to the membrane in the ER (purple) and the Golgi (orange). Notch is translated inside ER, where it is glycosylated by an O-fucosyltransferase O-Fut1 (light purple) and O-glucosyltransferase Rumi (yellow). Note the black circle on the Notch molecule in the ER; because Notch is not cleaved, the extracellular and intracellular domains are physically linked. Notch is then translocated into Golgi, where it is cleaved by Furin protease (scissors) at the S1 site and further modified by the N-acetylglucosaminyltransferase, Fringe. Note the red circle on the Notch molecule in the Golgi after S1 cleavage; the extracellular and intracellular domains are not physically linked Ligand-mediated activation - Notch (gray) interacts with the DSL ligands, Delta (blue) and Serrate (green), resulting in a series of proteolytic cleavage events induced by ligand binding. The S2 cleavage is mediated by ADAM protease (purple), whereas the S3/4 cleavage event is mediated by γ-secretase (g-secretase, in orange). Several studies also suggest that γ-secretase–mediated cleavage can occur inside endocytic compartment (shown in the light blue circle). Endocytic regulation of Notch receptor - full-length Notch can undergo endocytosis, leading to translocation of Notch into EEs, MVB, and lysosomes. From genetic data, several proteins have been identified to modulate this process, including Hrs and Bib, possibly during the EE-to-MVB transition of Notch, Lgd, and ESCRT complex, or during the MVB-to-lysosomes transition. These proteins further modulate Notch activity as described in the text. Dotted red arrow shows in mutants affect of trafficking from the MVB to the lysosome, or if Notch is not trafficked to the lumen of the lysosome, Notch can undergo γ-secretase cleavage, resulting in a Notch GOF phenotypes. (text from original figure legend)

Notch Receptors

Notch receptors belong to the Ankyrin repeat domain containing (ANKRD) gene family (242 members).

Table - Human Notch Family (Ankyrin repeat domain - ANKRD)
Approved Symbol	Approved Name	Previous Symbols	Synonyms	Chromosome	OMIM ID
NOTCH1	notch 1	TAN1		9q34.3	190198
NOTCH2	notch 2			1p12	600275
NOTCH3	notch 3	CADASIL	CASIL	19p13.12	600276
NOTCH4	notch 4	INT3		6p21.32	164951
Links: Notch | OMIM BMP2 | HGNC - ANKRD | Bmp Family | Notch Family | Sox Family | Tbx Family

Human BMP Family
Table - Human Notch Family (Ankyrin repeat domain - ANKRD) Approved Symbol Approved Name Previous Symbols Synonyms Chromosome OMIM ID NOTCH1 notch 1 TAN1 9q34.3 190198 NOTCH2 notch 2 1p12 600275 NOTCH3 notch 3 CADASIL CASIL 19p13.12 600276 NOTCH4 notch 4 INT3 6p21.32 164951     Links: Notch | OMIM BMP2 | HGNC - ANKRD | Bmp Family | Notch Family | Sox Family | Tbx Family

Links: HGNC - Ankyrin repeat domain containing (ANKRD) gene family

NOTCH3

• Notch3 activation retains mammary luminal cell in a nonproliferative state

Notch Ligands

• JAG1
• JAG2
• DLL1
• DLL3
• DLL4

Functions

Developmental patterning signal.

Early Development

Blastocyst

Mouse Blastocyst (32 cell stage) Fate
Inner cells	Outer cells
Angiomotin (Amot) phosphorylation at adherens junctions	Amot sequestered by cell polarization from basolateral adherens junctions
Hippo active	Hippo inactive
Notch inactive	Notch active
Cdx2 not expressed	Cdx2 expressed
ICM - inner cell mass fate	TE - trophectoderm fate
Hippo(TEAD4) and Notch(Cdx2) together appear regulate early blastocyst fate development.

Neural

Spinal Cord Development

Model of the embryonic rostro-caudal gradient of neurogenesis along the chicken spinal cord from the stem zone to the neurogenic neural tube summarising how DELTA-NOTCH signalling may be involved in these processes. Caudal to rostral decreasing FGF gradient, leads to Delta-1 expression decrease in cells that leave the stem zone (light blue) and move into the PNTZ where they intermingle with cells that do not express Delta-1. Generates differences in DELTA/NOTCH signalling between adjacent cells that may initiate lateral inhibition. Upregulation of Delta-1 in single NP cells which signal (blue arrows) and activate NOTCH signalling in adjacent cells, which as a consequence express Hes5 and are maintained in a proliferating state. Delta-1 expressing NP cell divides into two cells that express Tis21. Double Delta-1/Tis21 labelled NP down regulate the expression of Delta-1 as they reach the NZ and begin to divide in a neurogenic manner. One of the daughter cells upregulates Delta-1 expression and differentiates as a neuron while the other one, which receives NOTCH signalling (blue arrows), remains as neurogenic NP. Hensen node (HN), neural tube (NT), neurogenic zone (NZ), proliferation to neurogenesis transition zone (PNTZ), presomitic territory (PS), somite (S).

Hippocampus

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

"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."

Links: Hippocampus Development

Endoderm Development

Endoderm differentiates to form the respiratory airway epithelium and glands. This epithelium is continuously replaced through life from a basal cell pool of undifferentiated airway progenitors. A recent study has shown that the progenitor pool is regulated by the Notch3-Jagged signaling pathway. The mechanism appears dependent upon the availability of Jag1 and Jag2 (generating parabasal cells) that later activates Notch1 and Notch2 leading to a secretory-multiciliated cell fate.

L;inks: Respiratory System Development

Blood Vessel Development

NOTCH Signaling in the EndotheliumPubmedParser error: Invalid PMID, please check. (PMID: 29547401PMID29547401)

(a) A vascular sprout is characterized by a leading ‘tip’ cell followed by ‘stalk’ cells.

(b) Regulation of new sprouting during vascular expansion depends on integration of BMP signaling, NOTCH signaling and VEGF signaling.

(c) In adult vessels, NOTCH is responsible for maintaining endothelial quiescence and junctional integrity.

Muscle Regeneration

Notch signalling in muscle regeneration

Hypothalamus Development

Hypothalamus Development Gene Interaction Model

Links: Hypothalamus Development

Abnormalities

Alagille Syndrome

Mutations in the human homolog of Jagged-1 (JAG1) located on chromosome 20p12 cause Alagille Syndrome. Abnormalities are seen in gastrointestinal (liver cholestasis), cardiac (heart), renal (kidney), skeletal, ocular, and facial systems.

Links: Alagille Syndrome

References

Reviews

Reichrath J & Reichrath S. (2020). A Snapshot of the Molecular Biology of Notch Signaling: Challenges and Promises. Adv. Exp. Med. Biol. , 1227, 1-7. PMID: 32072495 DOI.

Amelio I, Grespi F, Annicchiarico-Petruzzelli M & Melino G. (2012). p63 the guardian of human reproduction. Cell Cycle , 11, 4545-51. PMID: 23165243 DOI.

Roemer K. (2012). Notch and the p53 clan of transcription factors. Adv. Exp. Med. Biol. , 727, 223-40. PMID: 22399351 DOI.

Andersen P, Uosaki H, Shenje LT & Kwon C. (2012). Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol. , 22, 257-65. PMID: 22397947 DOI.

Andersson ER, Sandberg R & Lendahl U. (2011). Notch signaling: simplicity in design, versatility in function. Development , 138, 3593-612. PMID: 21828089 DOI.

Search Pubmed

Search Bookshelf Notch

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• OMIM - NOTCH 1

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Cite this page: Hill, M.A. (2023, December 2) Embryology Developmental Signals - Notch. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Notch

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G