title: 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.
authors.affiliation: Section of Molecular Cell and Developmental Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Jiwoon
authors.initials: J
authors.lastname: Lee
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gross
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003103:Coloboma / Q000235:genetics* / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D009479:Neuropeptides; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C586443:bcl6aa protein, zebrafish; C571228:tp53 protein, zebrafish; C485179:vax1 protein, zebrafish; C586444:vax2 protein, zebrafish