Ubiquitin-mediated proteasome degradation regulates optic fissure fusion

Warlen Pereira Piedade, Sydney Veith, Jakub Konrad Famulski

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Optic fissure fusion is a critical event during retinal development. Failure of fusion leads to coloboma, a potentially blinding congenital disorder. Pax2a is an essential regulator of optic fissure fusion and the target of numerous morphogenetic pathways. In our current study, we examined the negative regulator of pax2a expression, Nz2, and the mechanism modulating Nlz2 activity during optic fissure fusion. Upregulation of Nlz2 in zebrafish embryos resulted in downregulation of pax2a expression and fissure fusion failure.Conversely, upregulation of pax2a expression also led to fissure fusion failure suggesting Pax2 levels require modulation to ensure proper fusion. Interestingly, we discovered Nlz2 is a target of the E3 ubiquitin ligase Siah.We show that zebrafish siah1 expression is regulated by Hedgehog signaling and that Siah1 can directly target Nlz2 for proteasomal degradation, in turn regulating the levels of pax2a mRNA. Finally, we show that both activation and inhibition of Siah activity leads to failure of optic fissure fusion dependent on ubiquitin-mediated proteasomal degradation of Nlz2. In conclusion, we outline a novel, proteasome-mediated degradation regulatory pathway involved in optic fissure fusion.

Original languageEnglish
Article numberbio044974
JournalBiology Open
Issue number6
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by start-up funds from the Department of Biology, University of Kentucky and the Career Starter Award Grant from the Knights Templar Eye Foundation to J.K.F. W.P.P. was supported by the Brazilian National Council for Scientific and Technological Development (CNPq) under grant number 202970/ 2014-0.

Publisher Copyright:
© 2019. Published by The Company of Biologists Ltd.


  • Coloboma
  • Nlz2
  • Optic fissure
  • Pax2
  • Proteasome
  • Retina
  • SIAH

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)
  • Agricultural and Biological Sciences (all)


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