RT Journal Article
SR Electronic
T1 TGFβ mediated structural remodeling facilitates optic fissure fusion and the necessity of BMP antagonism in this process
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 131599
DO 10.1101/131599
A1 Max D. Knickmeyer
A1 Juan L. Mateo
A1 Priska Eckert
A1 Eleni Roussa
A1 Belal Rahhal
A1 Aimee Zuniga
A1 Kerstin Krieglstein
A1 Joachim Wittbrodt
A1 Stephan Heermann
YR 2017
UL http://biorxiv.org/content/early/2017/04/28/131599.abstract
AB 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.We found a coloboma phenotype in mice with a targeted inactivation of the transforming growth factor 2 (TGFβ2). Here the optic fissure margins got in touch, however, failed to fuse. Transcriptomic analyses indicated TGFβ mediated ECM remodeling during optic fissure fusion. For functional analyses, we switched model systems and made use of zebrafish. We found TGFβ ligands expressed in the developing zebrafish eye, and the ligand binding receptor in the optic fissure. Using a new in vivo TGFβ signaling reporter, we also found active TGFβ signaling in the margins of the optic fissure. We addressed the function of Cadherin 6 (cdh6), one of the TGFβ 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 TGFβ 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.Summary statement TGFβ is crucial for optic fissure fusion, involving cdh6. TGFβ mediated optic fissure fusion is potentially hampered by BMP signaling, which is blocked by TGFβ induced BMP antagonists within the optic fissure margins.