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bioRxiv · 10.1101/131599

TGF(beta) Mediated Structural Remodeling Facilitates Optic Fissure Fusion And The Necessity Of BMP Antagonism In This Process

Knickmeyer, M. D.·Mateo, J. L.·Eckert, P.·Roussa, E.·Rahhal, B.·Zuniga, A.·Krieglstein, K.·Wittbrodt, J.·Heermann, S.
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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. Multiple factors are genetically linked to coloboma formation. However, especially the process of optic fissure fusion is still largely elusive on a cellular and molecular basis.\n\nWe found a coloboma phenotype in mice with a targeted inactivation of the transforming growth factor 2 (TGF{beta}2). Here the optic fissure margins got in touch, however, failed to fuse. Transcriptomic analyses indicated TGF{beta} mediated ECM remodeling during optic fissure fusion. For functional analyses, we switched model systems and made use of zebrafish. We found TGF{beta} ligands expressed in the developing zebrafish eye, and the ligand binding receptor in the optic fissure. Using a new in vivo TGF{beta} signaling reporter, we also found active TGF{beta} signaling in the margins of the optic fissure. We addressed the function of Cadherin 6 (cdh6), one of the TGF{beta} regulated genes, by knock down experiments in zebrafish and found a prominent coloboma phenotype. Cdh6 was often found involved in processes of epithelial to mesenchymal transition (EMT), strengthening our hypothesis that an EMT-like process is also necessary for optic fissure fusion. Furthermore, we found Gremlin 2b (grem2b) and Follistatin a (fsta), homologs of TGF{beta} regulated bone morphogenetic protein (BMP) antagonists, expressed in the optic fissure margins, indicating the necessity of a localized inhibition of BMP signaling. Finally, we show that induced BMP expression is sufficient to inhibit optic fissure fusion. Together with our previous findings this indicates a dual role of BMP signaling during optic fissure closure.\n\nSummary statementTGF{beta} is crucial for optic fissure fusion, involving cdh6. TGF{beta} mediated optic fissure fusion is potentially hampered by BMP signaling, which is blocked by TGF{beta} induced BMP antagonists within the optic fissure margins.

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Knickmeyer, M. D., Mateo, J. L., Eckert, P., Roussa, E., Rahhal, B., Zuniga, A., Krieglstein, K., Wittbrodt, J., Heermann, S.. 2017-04-28. TGF(beta) Mediated Structural Remodeling Facilitates Optic Fissure Fusion And The Necessity Of BMP Antagonism In This Process. https://doi.org/10.1101/131599

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