PUBLICATION

TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism

Authors

Knickmeyer, M.D., Mateo, J.L., Eckert, P., Roussa, E., Rahhal, B., Zuniga, A., Krieglstein, K., Wittbrodt, J., Heermann, S.

ID

ZDB-PUB-180330-3

Date

2018

Source

Open Biology 8(3): (Journal)

Registered Authors

Heermann, Stephan, Wittbrodt, Jochen

Keywords

BMP, ECM, TGFβ, coloboma, optic fissure fusion

MeSH Terms

Bone Morphogenetic Proteins/antagonists & inhibitors*
Disease Models, Animal
Zebrafish/metabolism
Extracellular Matrix/metabolism
Transforming Growth Factor beta2/genetics*
Zebrafish Proteins/metabolism
Signal Transduction
Mice
Intercellular Signaling Peptides and Proteins/metabolism
Follistatin/metabolism
Animals
Coloboma/drug therapy
Coloboma/genetics*
Gene Expression Profiling/methods*

(all 14)

PubMed

29593116 Full text @ Open Biol.

Abstract

The optic fissure is a transient gap in the developing vertebrate eye, which must be closed as development proceeds. A persisting optic fissure, coloboma, is a major cause for blindness in children. Although many genes have been linked to coloboma, the process of optic fissure fusion is still little appreciated, especially on a molecular level. We identified a coloboma in mice with a targeted inactivation of transforming growth factor β2 (TGFβ2). Notably, here the optic fissure margins must have touched, however failed to fuse. Transcriptomic analyses indicated an effect on remodelling of the extracellular matrix (ECM) as an underlying mechanism. TGFβ signalling is well known for its effect on ECM remodelling, but it is at the same time often inhibited by bone morphogenetic protein (BMP) signalling. Notably, we also identified two BMP antagonists among the downregulated genes. For further functional analyses we made use of zebrafish, in which we found TGFβ ligands expressed in the developing eye, and the ligand binding receptor in the optic fissure margins where we also found active TGFβ signalling and, notably, also gremlin 2b (grem2b) and follistatin a (fsta), homologues of the regulated BMP antagonists. We hypothesized that TGFβ is locally inducing expression of BMP antagonists within the margins to relieve the inhibition from its regulatory capacity regarding ECM remodelling. We tested our hypothesis and found that induced BMP expression is sufficient to inhibit optic fissure fusion, resulting in coloboma. Our findings can likely be applied also to other fusion processes, especially when TGFβ signalling or BMP antagonism is involved, as in fusion processes during orofacial development.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: SIS3	Prim-15	head grem2b expression decreased amount, abnormal	Fig. 3
AB	chemical treatment by environment: SIS3	Protruding-mouth	brain decreased size, abnormal	Fig. 2
AB	chemical treatment by environment: SIS3	Protruding-mouth	brain development decreased process quality, abnormal	Fig. 2
AB	chemical treatment by environment: SIS3	Protruding-mouth	closure of optic fissure arrested, abnormal	Fig. 2
AB	chemical treatment by environment: SIS3	Protruding-mouth	eye decreased size, abnormal	Fig. 2
AB	chemical treatment by environment: SIS3	Protruding-mouth	optic fissure closure incomplete, abnormal	Fig. 2
AB	chemical treatment by environment: SIS3	Protruding-mouth	optic furrow basement membrane ab1-lam labeling increased amount, abnormal	Fig. 2
AB	chemical treatment by environment: SIS3	Protruding-mouth	post-vent region curved dorsal, abnormal	Fig. 2
AB	heat shock	Protruding-mouth	closure of optic fissure occurrence, normal	Fig. 4
AB	heat shock	Protruding-mouth	optic fissure morphology, normal	Fig. 4

1 - 10 of 16

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Mutations / Transgenics

Allele	Construct	Type
af1Tg	Tg(hsp70l:bmp4,myl7:EGFP)	Transgenic Insertion
af2Tg	Tg(SBE:GFP-CAAX)	Transgenic Insertion
af3Tg	Tg(Mmu.Foxa2-cryaa:mCherry)	Transgenic Insertion

1 - 3 of 3

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
coloboma	af1Tg	heat shock	TAS

Sequence Targeting Reagents

Fish

Fish
AB
af1Tg
af2Tg; af3Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP
mCherry	EFG	mCherry

Mapping

Knickmeyer et al., 2018 ZDB-PUB-180330-3 PMID:29593116

TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism

Knickmeyer et al., 2018

ZDB-PUB-180330-3
PMID:29593116