PUBLICATION

Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression

Authors

Moleri, S., Mercurio, S., Pezzotta, A., D'Angelo, D., Brix, A., Plebani, A., Lini, G., Di Fuorti, M., Beltrame, M.

ID

ZDB-PUB-231002-148

Date

2023

Source

Cells 12(18): (Journal)

Registered Authors

Beltrame, Monica

Keywords

Sox18, SoxF transcription factors, VEGFC, lymphatic development, zebrafish

MeSH Terms

Zebrafish*/genetics
Zebrafish*/metabolism
Signal Transduction/physiology
Mice
Animals
Lymphatic Vessels*/metabolism
Transcription Factors/metabolism
Zebrafish Proteins*/metabolism
SOXF Transcription Factors*/genetics
SOXF Transcription Factors*/metabolism
Humans

(all 11)

PubMed

37759531 Full text @ Cells

Abstract

Mutations in the transcription factor-coding gene SOX18, the growth factor-coding gene VEGFC and its receptor-coding gene VEGFR3/FLT4 cause primary lymphedema in humans. In mammals, SOX18, together with COUP-TFII/NR2F2, activates the expression of Prox1, a master regulator in lymphatic identity and development. Knockdown studies have also suggested an involvement of Sox18, Coup-tfII/Nr2f2, and Prox1 in zebrafish lymphatic development. Mutants in the corresponding genes initially failed to recapitulate the lymphatic defects observed in morphants. In this paper, we describe a novel zebrafish sox18 mutant allele, sa12315, which behaves as a null. The formation of the lymphatic thoracic duct is affected in sox18 homozygous mutants, but defects are milder in both zygotic and maternal-zygotic sox18 mutants than in sox18 morphants. Remarkably, in sox18 mutants, the expression of the closely related sox7 gene is elevated where lymphatic precursors arise. Sox7 could thus mask the absence of a functional Sox18 protein and account for the mild lymphatic phenotype in sox18 mutants, as shown in mice. Partial knockdown of vegfc exacerbates lymphatic defects in sox18 mutants, making them visible in heterozygotes. Our data thus reinforce the genetic interaction between Sox18 and Vegfc in lymphatic development, previously suggested by knockdown studies, and highlight the ability of Sox7 to compensate for Sox18 lymphatic dysfunction.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
cdh5	sox18^{sa12315/sa12315} + MO5-sox7	standard conditions	Prim-15		endothelial cell	ISH	Figure 1
cdh5	WT + MO5-sox7	standard conditions	Prim-15		endothelial cell	ISH	Figure 1
plvapb	sox18^{sa12315/sa12315} + MO5-sox7	standard conditions	Prim-15		endothelial cell	ISH	Figure 1
plvapb	WT + MO5-sox7	standard conditions	Prim-15		endothelial cell	ISH	Figure 1
sox17	nz101Tg	standard conditions	Prim-5		dorsal aorta	ISH	Figure S5
sox17	nz101Tg	standard conditions	Prim-5	Not Detected	posterior cardinal vein	ISH	Figure S5
sox17	sox18^{sa12315/sa12315}; nz101Tg	standard conditions	Prim-5		dorsal aorta	ISH	Figure S5
sox17	sox18^{sa12315/sa12315}; nz101Tg	standard conditions	Prim-5	Not Detected	posterior cardinal vein	ISH	Figure S5
sox18	nz101Tg	standard conditions	Prim-5		dorsal aorta	ISH	Figure S5
sox18	nz101Tg	standard conditions	Prim-5		intersegmental vessel	ISH	Figure S5

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
sox18^sa12315/+; y1Tg	standard conditions	Day 5	thoracic duct amount, normal	Figure 3
sox18^sa12315/+; y1Tg + MO2-vegfc	standard conditions	Day 5	lymphangiogenesis disrupted, abnormal	Figure 3
sox18^sa12315/+; y1Tg + MO2-vegfc	standard conditions	Day 5	thoracic duct decreased amount, abnormal	Figure 3
sox18^sa12315/+; y1Tg + MO2-vegfc	standard conditions	Day 5	thoracic duct hypoplastic, abnormal	Figure 3
sox18^sa12315/+; y1Tg + MO2-vegfc	standard conditions	Day 5	thoracic duct malformed, abnormal	Figure 3
sox18^{sa12315/sa12315}	standard conditions	Prim-15	posterior cardinal vein sox7 expression increased amount, abnormal	Figure S4
sox18^{sa12315/sa12315} + MO5-sox7	standard conditions	Prim-15	endothelial cell plvapb expression decreased amount, abnormal	Figure 1
sox18^{sa12315/sa12315} + MO5-sox7	standard conditions	Protruding-mouth	blood circulation disrupted, abnormal	Figure 1
sox18^{sa12315/sa12315}; nz101Tg	standard conditions	Prim-5	posterior cardinal vein sox7 expression increased amount, abnormal	Figure 4
sox18^{sa12315/sa12315}; nz101Tg	standard conditions	Day 5	lymphangiogenesis disrupted, abnormal	Figure 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
nz101Tg	Tg(-5.2lyve1b:DsRed)	Transgenic Insertion
sa12315		Point Mutation	sox18
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion
y171Tg	Tg(kdrl:mCherry-CAAX)	Transgenic Insertion
y251Tg	Tg(mrc1a:EGFP)	Transgenic Insertion

1 - 5 of 5

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
sox7	MO5-sox7	MRPHLNO
sox18	MO7-sox18	MRPHLNO
vegfc	MO2-vegfc	MRPHLNO

Fish

Fish
nz101Tg
nz101Tg + MO7-sox18
sox18^{sa12315/sa12315}
sox18^{sa12315/sa12315} + MO5-sox7
sox18^{sa12315/sa12315}; nz101Tg
sox18^{sa12315/sa12315}; y1Tg
sox18^{sa12315/sa12315}; y1Tg
sox18^{sa12315/sa12315}; y1Tg + MO2-vegfc
sox18^{sa12315/sa12315}; y171Tg; y251Tg
sox18^sa12315/+; y1Tg

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
mCherry	EFG	mCherry

Mapping

Moleri et al., 2023 ZDB-PUB-231002-148 PMID:37759531

Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression

Moleri et al., 2023

ZDB-PUB-231002-148
PMID:37759531