Difference between revisions of "Developmental Signals - Nodal"

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{{Header}}
 
{{Header}}
 
==Introduction==
 
==Introduction==
[[File:Notch structure cartoon.jpg|thumb|350px|alt=Notch structure cartoon|Notch structure cartoon<ref name=PMID19255248><pubmed>19255248</pubmed></ref>]]
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Nodal  is a member of the TGF-beta family and together with Lefty both are involved in the initial left-right (L-R) patterning of the axis of the embryo during [[gastrulation]]. This patterning signal is later used for many cell fate developmental processes. This patterning role was first established in mouse and zebrafish models, the human homolog was first identified in 1997.{{#pmid:9354794|PMID9354794}}
The nodal 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.
 
  
  
{{Notch links}}
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Left-right (L-R) asymmetry include the position on the left side of the heart and spleen and the development of the curvature of the stomach.
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[[File:Mouse left-right axis 02.jpg|800px]]
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Mouse ([[:Category:Mouse E8.0|E8.0]]) left-right axis formation.{{#pmid:28182636|PMID28182636}} Nodal activity and expression (dark blue).
  
 
{{Factor Links}}
 
{{Factor Links}}
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|-bgcolor="F5FAFF"  
 
|-bgcolor="F5FAFF"  
 
|
 
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* <ref name=PMID27226324><pubmed>27226324</pubmed></ref>
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* '''Leftward Flow Determines Laterality in Conjoined Twins'''{{#pmid:28190730|PMID28190730}} "Conjoined twins fused at the thorax display an enigmatic left-right defect: although left twins are normal, laterality is disturbed in one-half of right twins. Molecularly, this randomization corresponds to a lack of asymmetric Nodal cascade induction in right twins. We studied leftward flow at the left-right organizer (LRO) in thoracopagus twins in Xenopus, which displayed a duplicated, fused, and ciliated LRO. Cilia were motile and produced a leftward flow from the right LRO margin of the right to the left margin of the left twin. Motility was required for correct laterality in left twins, as knockdown of dynein motor dnah9 prevented Nodal cascade induction. Nodal was rescued by parallel knockdown of the inhibitor dand5  on the left side of the left twin. Lack of Nodal induction in the right twin, despite the presence of flow, was due to insufficient suppression of dand5. Knockdown of dand5 at the center of the fused LRO resulted in asymmetric Nodal cascade induction in the right twin as well. Manipulation of leftward flow and dand5 in a targeted and sided manner induced the Nodal cascade in a predictable manner, in the left twin, the right one, both, or neither. Laterality in conjoined twins thus was determined by cilia-driven leftward fluid flow like in single embryos, which solves a century-old riddle, as the phenomenon was already studied by some of the founders of experimental embryology."  [[Abnormal_Development_-_Twinning|Twinning]] | [[Frog Development]]
 
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{| class="wikitable mw-collapsible mw-collapsed"
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==Nodal Signaling==
 
==Nodal Signaling==
 
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Nodal represents a family of transmembrane receptors passing only once through the plasma membrane. Nodal acts through SMAD2 dependent and independent intracellular pathways.
==Nodal Receptors==
 
  
  
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Developmental patterning signal.
 
Developmental patterning signal.
  
===Spinal Cord Development===
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===Left-Right Axis 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.<ref><pubmed>18000541</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001169 PLoS ONE]</ref>
 
* 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).
 
  
| [[File:Spinal cord delta notch model.png|500px]]
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{|  
|}
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|-
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| colspan=5|Model mouse ([[:Category:Mouse E8.0|E8.0]]) Left-Right Axis{{#pmid:28182636|PMID28182636}}
  
===Endoderm Development===
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Gastrula stage - Initially perinodal crown cells symmetrically express Nodal, Wnt and their antagonist Cerberus like-2 (Cerl2). Nodal activity and expression (dark blue).
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<ref name=PMID25564622><pubmed>25564622</pubmed></ref> 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]]
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[[File:Mouse left-right axis 02.jpg|800px]]
===Mesoderm Development===
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|-
 
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| 1-somite stage Cerl2 expression (green) becomes asymmetric with reduced expression on the left side of the node in response to fluid flow. With reduced expression of its antagonist on the left, Nodal activity and expression (dark blue) increases on the left side and decreases on the right.
===Cartilage Development===
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| 2-somite stage wild type embryos, Nodal induce Nodal expression in the L-LPM (left lateral plate mesoderm)
 
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| 3-somite stage robust expression of Nodal along with Lefty1 and Lefty2 (light blue) is detected in the L-LPM and Lefty1 in the midline (light blue).
===Muscle Regeneration===
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| 4-somite stage embryos Nodal expression is reduced but Lefty1 and Lefty2 are strongly expressed in the L-LPM. Lefty1 expression in the midline and Cerl2 around the node inhibits Nodal signaling in the R-LPM.  
 
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|}
[[File:Notch signalling in muscle regeneration cartoon.jpg|600px]]
 
  
Notch signalling in muscle regeneration<ref><pubmed>24472470</pubmed>| [http://www.biomedcentral.com/1471-213X/14/2 BMC Dev Biol.]</ref>
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:'''Links:''' [[:File:Mouse left-right axis 02.jpg|wildtype alone]] | [[Developmental Signals - Nodal|Nodal]] | [[Developmental Mechanism - Axes Formation|Axes Formation]] | [[Gastrulation]] | [[:Category:Mouse E8.0|Mouse E8.0]] | [[Mouse Development]]
  
===Hypothalamus Development===
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(Theiler Stage 12a First Somites unturned embryo with first appearance of somite pairs 1-4 somites. The allantois extends further into the exocoelom and the maxillary components of the 1st branchial arch become prominent. The preotic sulcus is visible in the 2-3 somite embryo. The cardiogenic plate begins to form and the foregut pocket is clearly visible. Embryonic age = 8 dpc (range 7.5-8.75 dpc) 1-7 somite pairs
  
[[File:Hypothalamus gene interaction model.jpg|600px]]
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===Stomach Development===
  
Hypothalamus Development Gene Interaction Model<ref name=PMID>24360028<pubmed>24360028</pubmed>| [http://www.neuraldevelopment.com/content/8//25 Neural Dev.]</ref>
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* '''Stomach curvature is generated by left-right asymmetric gut morphogenesis'''{{#pmid:28242610|PMID28242610}} "Left-right (LR) asymmetry is a fundamental feature of internal anatomy, yet the emergence of morphological asymmetry remains one of the least understood phases of organogenesis. Asymmetric rotation of the intestine is directed by forces outside the gut, but the morphogenetic events that generate anatomical asymmetry in other regions of the digestive tract remain unknown. Here, we show in mouse and Xenopus that the mechanisms that drive the curvature of the stomach are intrinsic to the gut tube itself. The left wall of the primitive stomach expands more than the right wall, as the left epithelium becomes more polarized and undergoes radial rearrangement. These asymmetries exist across several species, and are dependent on LR patterning genes, including Foxj1, Nodal and Pitx2 Our findings have implications for how LR patterning manifests distinct types of morphological asymmetries in different contexts."
  
:'''Links:''' [[Endocrine_-_Hypothalamus_Development|Hypothalamus Development]]
 
  
 
==Abnormalities==
 
==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]]
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:'''Links:'''  
 
==References==
 
==References==
 
<references/>
 
<references/>
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===Reviews===
 
===Reviews===
<pubmed></pubmed>
 
<pubmed></pubmed>
 
<pubmed></pubmed>
 
<pubmed></pubmed>
 
<pubmed></pubmed>
 
<pubmed></pubmed>
 
  
 
===Search Pubmed===
 
===Search Pubmed===
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{{External Links}}
 
{{External Links}}
  
* OMIM - [http://www.ncbi.nlm.nih.gov/omim/190198 NOTCH 1]
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* Online Mendelian Inheritance in Man (OMIM) [https://omim.org/entry/601265 NODAL] | [https://omim.org/entry/603037 LEFTY1] | [https://omim.org/entry/601877 LEFTY2] | [https://omim.org/entry/609157 NODAL MODULATOR 1; NOMO1] | [https://omim.org/entry/609158 NODAL MODULATOR 2; NOMO2] | [https://omim.org/entry/609159 NODAL MODULATOR 3; NOMO3] |
 
 
 
 
 
 
  
 
{{Glossary}}
 
{{Glossary}}

Latest revision as of 21:47, 19 March 2018

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Introduction

Nodal is a member of the TGF-beta family and together with Lefty both are involved in the initial left-right (L-R) patterning of the axis of the embryo during gastrulation. This patterning signal is later used for many cell fate developmental processes. This patterning role was first established in mouse and zebrafish models, the human homolog was first identified in 1997.[1]


Left-right (L-R) asymmetry include the position on the left side of the heart and spleen and the development of the curvature of the stomach.


Mouse left-right axis 02.jpg

Mouse (E8.0) left-right axis formation.[2] Nodal activity and expression (dark blue).

Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

Some Recent Findings

  • Leftward Flow Determines Laterality in Conjoined Twins[3] "Conjoined twins fused at the thorax display an enigmatic left-right defect: although left twins are normal, laterality is disturbed in one-half of right twins. Molecularly, this randomization corresponds to a lack of asymmetric Nodal cascade induction in right twins. We studied leftward flow at the left-right organizer (LRO) in thoracopagus twins in Xenopus, which displayed a duplicated, fused, and ciliated LRO. Cilia were motile and produced a leftward flow from the right LRO margin of the right to the left margin of the left twin. Motility was required for correct laterality in left twins, as knockdown of dynein motor dnah9 prevented Nodal cascade induction. Nodal was rescued by parallel knockdown of the inhibitor dand5 on the left side of the left twin. Lack of Nodal induction in the right twin, despite the presence of flow, was due to insufficient suppression of dand5. Knockdown of dand5 at the center of the fused LRO resulted in asymmetric Nodal cascade induction in the right twin as well. Manipulation of leftward flow and dand5 in a targeted and sided manner induced the Nodal cascade in a predictable manner, in the left twin, the right one, both, or neither. Laterality in conjoined twins thus was determined by cilia-driven leftward fluid flow like in single embryos, which solves a century-old riddle, as the phenomenon was already studied by some of the founders of experimental embryology." Twinning | Frog Development
More recent papers  
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Search term: Nodal

<pubmed limit=5>Nodal</pubmed>

Older papers  
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See also the Discussion Page for other references listed by year and References on this current page.


Nodal Signaling

Nodal represents a family of transmembrane receptors passing only once through the plasma membrane. Nodal acts through SMAD2 dependent and independent intracellular pathways.


Nodal Ligands

Functions

Developmental patterning signal.

Left-Right Axis Development

Model mouse (E8.0) Left-Right Axis[2]

Gastrula stage - Initially perinodal crown cells symmetrically express Nodal, Wnt and their antagonist Cerberus like-2 (Cerl2). Nodal activity and expression (dark blue).

Mouse left-right axis 02.jpg

1-somite stage Cerl2 expression (green) becomes asymmetric with reduced expression on the left side of the node in response to fluid flow. With reduced expression of its antagonist on the left, Nodal activity and expression (dark blue) increases on the left side and decreases on the right. 2-somite stage wild type embryos, Nodal induce Nodal expression in the L-LPM (left lateral plate mesoderm) 3-somite stage robust expression of Nodal along with Lefty1 and Lefty2 (light blue) is detected in the L-LPM and Lefty1 in the midline (light blue). 4-somite stage embryos Nodal expression is reduced but Lefty1 and Lefty2 are strongly expressed in the L-LPM. Lefty1 expression in the midline and Cerl2 around the node inhibits Nodal signaling in the R-LPM.
Links: wildtype alone | Nodal | Axes Formation | Gastrulation | Mouse E8.0 | Mouse Development

(Theiler Stage 12a First Somites unturned embryo with first appearance of somite pairs 1-4 somites. The allantois extends further into the exocoelom and the maxillary components of the 1st branchial arch become prominent. The preotic sulcus is visible in the 2-3 somite embryo. The cardiogenic plate begins to form and the foregut pocket is clearly visible. Embryonic age = 8 dpc (range 7.5-8.75 dpc) 1-7 somite pairs

Stomach Development

  • Stomach curvature is generated by left-right asymmetric gut morphogenesis[4] "Left-right (LR) asymmetry is a fundamental feature of internal anatomy, yet the emergence of morphological asymmetry remains one of the least understood phases of organogenesis. Asymmetric rotation of the intestine is directed by forces outside the gut, but the morphogenetic events that generate anatomical asymmetry in other regions of the digestive tract remain unknown. Here, we show in mouse and Xenopus that the mechanisms that drive the curvature of the stomach are intrinsic to the gut tube itself. The left wall of the primitive stomach expands more than the right wall, as the left epithelium becomes more polarized and undergoes radial rearrangement. These asymmetries exist across several species, and are dependent on LR patterning genes, including Foxj1, Nodal and Pitx2 Our findings have implications for how LR patterning manifests distinct types of morphological asymmetries in different contexts."


Abnormalities

Links:

References

  1. Gebbia M, Ferrero GB, Pilia G, Bassi MT, Aylsworth A, Penman-Splitt M, Bird LM, Bamforth JS, Burn J, Schlessinger D, Nelson DL & Casey B. (1997). X-linked situs abnormalities result from mutations in ZIC3. Nat. Genet. , 17, 305-8. PMID: 9354794 DOI.
  2. 2.0 2.1 Sugrue KF & Zohn IE. (2017). Mechanism for generation of left isomerism in Ccdc40 mutant embryos. PLoS ONE , 12, e0171180. PMID: 28182636 DOI.
  3. Tisler M, Thumberger T, Schneider I, Schweickert A & Blum M. (2017). Leftward Flow Determines Laterality in Conjoined Twins. Curr. Biol. , 27, 543-548. PMID: 28190730 DOI.
  4. Davis A, Amin NM, Johnson C, Bagley K, Ghashghaei HT & Nascone-Yoder N. (2017). Stomach curvature is generated by left-right asymmetric gut morphogenesis. Development , 144, 1477-1483. PMID: 28242610 DOI.


Reviews

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Cite this page: Hill, M.A. (2021, January 16) Embryology Developmental Signals - Nodal. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Nodal

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