PUBLICATION

Conserved regulation of Nodal-mediated left-right patterning in zebrafish and mouse

Authors

Montague, T.G., Gagnon, J.A., Schier, A.F.

ID

ZDB-PUB-181118-19

Date

2018

Source

Development (Cambridge, England) 145(24): (Journal)

Registered Authors

Schier, Alexander

Keywords

Cerl2, Dand5, Left-right patterning, Lefty, Nodal, Southpaw

MeSH Terms

Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Mice
Nodal Protein/genetics
Nodal Protein/metabolism*
Time Factors
Protein Multimerization
Gene Expression Regulation, Developmental
Animals
Mutation/genetics
Nodal Signaling Ligands/genetics
Nodal Signaling Ligands/metabolism*
Body Patterning*
Zebrafish/embryology*
Zebrafish/genetics
Zebrafish/metabolism*
Models, Biological

(all 17)

PubMed

30446628 Full text @ Development

Abstract

The TGF-beta signal Nodal is the major effector of left-right axis development. In mice, Nodal forms heterodimers with Gdf1 and is restricted to the left side by Cerl2/Dand5. Nodal expression then propagates up the lateral plate mesoderm (LPM) by autoinduction, while Lefty1 inhibition maintains it on the left. Studies in zebrafish have suggested some parallels, but also differences, between the modes of left-right patterning in mouse and zebrafish. To address these discrepancies, we generated single and double zebrafish mutants for spaw (the Nodal ortholog), dand5 (the Cerl2 ortholog) and lefty1, and performed biochemical and activity assays with Spaw and Vg1/Gdf3 (the Gdf1 ortholog). Contrary to previous findings, spaw mutants failed to initiate spaw expression in the LPM, and asymmetric heart looping was absent, similar to mouse Nodal mutants. In blastoderm assays, Vg1 and Spaw were interdependent for inducing target gene expression, and contrary to previous results, formed heterodimers. Loss of Dand5 or Lefty1 caused bilateral spaw expression, similar to mouse mutants, and premature expression and propagation of spaw in the LPM. Finally, Lefty1 inhibition of Nodal activity could be replaced by uniform exposure to a Nodal signaling inhibitor. Collectively, these results indicate that Dand5 activity biases Spaw-Vg1 heterodimer activity to the left, Spaw around Kupffer's vesicle induces the expression of spaw in the LPM, and global Nodal inhibition maintains the left bias of Spaw activity, demonstrating conservation between zebrafish and mouse mechanisms of left-right patterning.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
dand5^a204/a204 (AB/TL)	standard conditions	5-9 somites	lateral plate mesoderm spaw expression increased amount, abnormal	Fig. 3
dand5^a204/a204 (AB/TL)	standard conditions	10-13 somites	lateral plate mesoderm left side spaw expression mislocalised, abnormal	Fig. 1
dand5^a204/a204 (AB/TL)	standard conditions	10-13 somites	lateral plate mesoderm right side spaw expression mislocalised, abnormal	Fig. 3
dand5^a204/a204 (AB/TL)	standard conditions	10-13 somites	lateral plate mesoderm right side spaw expression mislocalised, abnormal	Fig. 1
dand5^a204/a204 (AB/TL)	standard conditions	10-13 somites	notochord lft1 expression increased amount, abnormal	Fig. 1
dand5^a204/a204 (AB/TL)	standard conditions	10-13 somites	notochord lft1 expression increased distribution, abnormal	Fig. 1
dand5^a204/a204 (AB/TL)	standard conditions	14-19 somites	lateral plate mesoderm right side spaw expression mislocalised, abnormal	Fig. 3
dand5^a204/a204 (AB/TL)	standard conditions	20-25 somites	heart primordium right side lft2 expression mislocalised, abnormal	Fig. 1
dand5^a204/a204 (AB/TL)	standard conditions	20-25 somites	whole organism medial region lft1 expression increased amount, abnormal	Fig. 1
dand5^a204/a204 (AB/TL)	standard conditions	20-25 somites	whole organism medial region lft1 expression increased distribution, abnormal	Fig. 1

1 - 10 of 82

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
a145	Indel	lft1
a165	Small Deletion	gdf3
a204	Small Deletion	dand5
a205	Small Deletion	spaw

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
dand5	CRISPR1-dand5	CRISPR
spaw	CRISPR2-spaw	CRISPR
spaw	CRISPR3-spaw	CRISPR

Fish

Fish
AB/TL
dand5^a204/a204 (AB/TL)
dand5^a204/a204; lft1^a145/a145 (AB/TL)
dand5^a204/a204; spaw^a205/a205 (AB/TL)
lft1^a145/a145 (AB/TL)
spaw^a205/a205 (AB/TL)
spaw^a205/a205; lft1^a145/a145 (AB/TL)

1 - 7 of 7

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Antibodies

Orthology

Engineered Foreign Genes

Mapping

Montague et al., 2018 ZDB-PUB-181118-19 PMID:30446628

Conserved regulation of Nodal-mediated left-right patterning in zebrafish and mouse

Montague et al., 2018

ZDB-PUB-181118-19
PMID:30446628