Bcl6a function is required during optic cup formation to prevent p53-dependent apoptosis and colobomata

Abstract

Mutations in BCOR (Bcl6 corepressor) are found in patients with oculo-facio-cardio-dental (OFCD) syndrome, a congenital disorder affecting visual system development, and loss-of-function studies in zebrafish and Xenopus demonstrate a role for Bcor during normal optic cup development in preventing colobomata. The mechanism whereby BCOR functions during eye development to prevent colobomata is not known, but in other contexts it serves as a transcriptional corepressor that potentiates transcriptional repression by B cell leukemia/lymphoma 6 (BCL6). Here, we have explored the function of the zebrafish ortholog of Bcl6, Bcl6a, during eye development, and our results demonstrate that Bcl6a, like Bcor, is required to prevent colobomata during optic cup formation. Our data demonstrate that Bcl6a acts downstream of Vax1 and Vax2, known regulators of ventral optic cup formation and choroid fissure closure, and that bcl6a is a direct target of Vax2. Together, this regulatory network functions to repress p53 expression and thereby suppress apoptosis in the developing optic cup. Furthermore, our data demonstrate that Bcl6a functions cooperatively with Bcor, Rnf2 and Hdac1 in a common gene regulatory network that acts to repress p53 and prevent colobomata. Together, these data support a model in which p53-dependent apoptosis needs to be tightly regulated for normal optic cup formation and that Bcl6a, Bcor, Rnf2 and Hdac1 activities mediate this regulation.

Zebrafish mab21l2 mutants possess severe defects in optic cup morphogenesis, lens and cornea development

“…Elevated cell death in the optic stalk is also known to contribute to colobomas . Thus, we next used TUNEL staining to assess the presence of dying cells in the optic stalk of mab21l2 −/− mutants at 22SS and 26SS (Figure ).…”

Bcl6aa and bcl6ab are ubiquitously expressed and are inducible by lipopolysaccharide and polyI:C in adult tissues of medaka Oryzias latipes

“…A strong expression of bcl6aa was detected in the developing eyes of medaka embryos in 5 dpf suggested the major function of Bcl6aa in eye development. Bcl6aa has been identified in downstream of Vax2 and functioning together with Vax2, Bcor, Rnf2, and Hdac1 to repress p53 expression, and thereby suppress apoptosis to prevent colobomata in zebrafish (J. Lee et al, ). At the same time, bcl6ab was ubiquitously expressed in the embryos referred to the divergence in the function of Bcl6aa and Bcl6ab during organogenesis in medaka.…”

“…The homologs of Bcl6 had been reported in fugu Takifugu rubripes Temminck and Schlegel (Ohtani, Miyadai, & Hiroishi, ) and zebrafish Danio rerio Hamilton (Hu et al, ; J. Lee, Lee., & Gross, ). Fugu bcl6 ( bcl6aa ) was detected in the tissues like kidney, intestine, and spleen.…”

“…In vitro study indicated fugu bcl6 functioned as a repression factor for its target genes (Ohtani & Miyadai, ). Zebrafish bcl6a (bcl6aa) was reported necessary for eye development (J. Lee et al, ), and was identified as the hub factor for cold response (Hu et al, ).…”

Evidence of Germline Mosaicism for a Novel <b><i>BCOR</i></b> Mutation in Two Indian Sisters with Oculo-Facio-Cardio-Dental Syndrome

“…It has also been identified as a negative regulator of osteo-dentiogenic capacity of mesenchymal stem cells [Fan et al, 2009]. More recent data indicate a cooperative function of the zebrafish orthologs Bcor and Bcl6a in normal optic cup formation through regulating p53-dependent apoptosis [Lee et al, 2013].…”