TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism
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...
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doaj-e64766aecf6345faa15972d5a6a577502020-11-25T03:00:08ZengThe Royal SocietyOpen Biology2046-24412018-03-018310.1098/rsob.170134170134TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonismMax D. KnickmeyerJuan L. MateoPriska EckertEleni RoussaBelal RahhalAimee ZunigaKerstin KrieglsteinJoachim WittbrodtStephan HeermannThe 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.https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.170134optic fissure fusioncolobomatgfβbmpecm |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Max D. Knickmeyer Juan L. Mateo Priska Eckert Eleni Roussa Belal Rahhal Aimee Zuniga Kerstin Krieglstein Joachim Wittbrodt Stephan Heermann |
spellingShingle |
Max D. Knickmeyer Juan L. Mateo Priska Eckert Eleni Roussa Belal Rahhal Aimee Zuniga Kerstin Krieglstein Joachim Wittbrodt Stephan Heermann TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism Open Biology optic fissure fusion coloboma tgfβ bmp ecm |
author_facet |
Max D. Knickmeyer Juan L. Mateo Priska Eckert Eleni Roussa Belal Rahhal Aimee Zuniga Kerstin Krieglstein Joachim Wittbrodt Stephan Heermann |
author_sort |
Max D. Knickmeyer |
title |
TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism |
title_short |
TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism |
title_full |
TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism |
title_fullStr |
TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism |
title_full_unstemmed |
TGFβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism |
title_sort |
tgfβ-facilitated optic fissure fusion and the role of bone morphogenetic protein antagonism |
publisher |
The Royal Society |
series |
Open Biology |
issn |
2046-2441 |
publishDate |
2018-03-01 |
description |
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. |
topic |
optic fissure fusion coloboma tgfβ bmp ecm |
url |
https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.170134 |
work_keys_str_mv |
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