PUBLICATION

The mediator complex subunit Med10 regulates heart valve formation in zebrafish by controlling Tbx2b-mediated Has2 expression and cardiac jelly formation

Authors

Just, S., Hirth, S., Berger, I.M., Fishman, M.C., Rottbauer, W.

ID

ZDB-PUB-160628-12

Date

2016

Source

Biochemical and Biophysical Research Communications 477(4): 581-8 (Journal)

Registered Authors

Berger, Ina, Fishman, Mark C., Hirth, Sophia, Just, Steffen, Rottbauer, Wolfgang

Keywords

Foxn4, Has2, Med10, Tbx2b, Valve formation, Zebrafish

MeSH Terms

T-Box Domain Proteins/metabolism
T-Box Domain Proteins/physiology*
Heart Valves/embryology*
Heart Valves/metabolism
Signal Transduction
Mutation
Glucuronosyltransferase/metabolism*
Mediator Complex/physiology*
Zebrafish Proteins/metabolism*
Zebrafish Proteins/physiology*
Zebrafish/embryology*
Zebrafish/genetics
Animals
Forkhead Transcription Factors/metabolism

(all 14)

PubMed

27343557 Full text @ Biochem. Biophys. Res. Commun.

Abstract

In search for novel key regulators of cardiac valve formation, we isolated the zebrafish cardiac valve mutant ping pong (png). We find that an insertional promoter mutation within the zebrafish mediator complex subunit 10 (med10) gene is leading to impaired heart valve formation. Expression of the T-box transcription factor 2b (Tbx2b), known to be essential in cardiac valve development, is severely reduced in png mutant hearts. We demonstrate here that transient reconstitution of Tbx2b expression rescues AV canal development in png mutant zebrafish. By contrast, overexpression of Forkhead box N4 (Foxn4), a known upstream regulator of Tbx2b, is not capable to reconstitute tbx2b expression and heart valve formation in Med10-deficient png mutant hearts. Interestingly, hyaluronan synthase 2 (has2), a known downstream target of Tbx2 and producer of hyaluronan (HA) - a major ECM component of the cardiac jelly and critical for proper heart valve development - is completely absent in ping pong mutant hearts. We propose here a rather unique role of Med10 in orchestrating cardiac valve formation by mediating Foxn4 dependent tbx2b transcription, the expression of Has2 and subsequently the proper development of the cardiac jelly.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
bmp4	med10^m683/m683	standard conditions	Protruding-mouth		atrium	ISH	Fig. S2
bmp4	med10^m683/m683	standard conditions	Protruding-mouth		cardiac ventricle	ISH	Fig. S2
bmp4	WT	standard conditions	Protruding-mouth		atrioventricular canal	ISH	Fig. S2
bmp4	WT	standard conditions	Protruding-mouth		bulbus arteriosus	ISH	Fig. S2
bmp4	WT	standard conditions	Protruding-mouth		sinus venosus	ISH	Fig. S2
has2	med10^m683/m683	standard conditions	Protruding-mouth	Not Detected	atrioventricular canal	ISH	Fig. 4
has2	med10^m683/m683	standard conditions	Long-pec	Not Detected	atrioventricular canal	ISH	Fig. 4
has2	WT	standard conditions	Protruding-mouth		atrioventricular canal	ISH	Fig. 4
has2	WT	standard conditions	Long-pec		atrioventricular canal	ISH	Fig. 4
notch1b	med10^m683/m683	standard conditions	Protruding-mouth		atrium	ISH	Fig. S2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-med10	standard conditions	Protruding-mouth	atrioventricular ring morphology, abnormal	Fig. S3
WT + MO1-med10	standard conditions	Protruding-mouth	endocardial cushion absent, abnormal	Fig. S3
WT + MO2-foxn4	standard conditions	Protruding-mouth	atrioventricular canal development disrupted, abnormal	Fig. 3
WT + MO2-foxn4	standard conditions	Protruding-mouth	heart valve morphology, abnormal	Fig. 3
WT + MO3-med10	standard conditions	Protruding-mouth	atrioventricular ring morphology, abnormal	Fig. S3
WT + MO3-med10	standard conditions	Protruding-mouth	endocardial cushion absent, abnormal	Fig. S3
med10^m683/+ + MO2-foxn4	standard conditions	Protruding-mouth	atrioventricular canal development disrupted, abnormal	Fig. 3
med10^m683/+ + MO2-foxn4	standard conditions	Protruding-mouth	atrioventricular canal endocardial cushion absent, abnormal	Fig. 3
med10^m683/+ + MO2-foxn4	standard conditions	Protruding-mouth	atrioventricular ring morphology, abnormal	Fig. 3
med10^m683/+ + MO2-foxn4	standard conditions	Protruding-mouth	atrioventricular valve absent, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
m683		Insertion	med10
w34Tg	Tg(hsp70l:wnt8a-GFP)	Transgenic Insertion
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
foxn4	MO2-foxn4	MRPHLNO
med10	MO1-med10	MRPHLNO
med10	MO3-med10	MRPHLNO

Fish

Fish
med10^m683/m683
med10^m683/m683; y1Tg
med10^m683/+ + MO2-foxn4
WT
WT + MO1-med10
WT + MO2-foxn4
WT + MO3-med10

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Just et al., 2016 ZDB-PUB-160628-12 PMID:27343557

The mediator complex subunit Med10 regulates heart valve formation in zebrafish by controlling Tbx2b-mediated Has2 expression and cardiac jelly formation

Just et al., 2016

ZDB-PUB-160628-12
PMID:27343557