PUBLICATION
Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling
- Authors
- George, A., Lee, J., Liu, J., Kim, S., Brooks, B.P.
- ID
- ZDB-PUB-221229-4
- Date
- 2022
- Source
- Developmental Dynamics : an official publication of the American Association of Anatomists 252(4): 495-509 (Journal)
- Registered Authors
- Brooks, Brian P., Liu, James
- Keywords
- Coloboma, RERE and SHH, optic fissure, optic stalk
- MeSH Terms
-
- Animals
- Carrier Proteins/metabolism
- Coloboma*/genetics
- Coloboma*/metabolism
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Humans
- Retina/metabolism
- Signal Transduction/physiology
- Zebrafish*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 36576487 Full text @ Dev. Dyn.
Citation
George, A., Lee, J., Liu, J., Kim, S., Brooks, B.P. (2022) Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling. Developmental Dynamics : an official publication of the American Association of Anatomists. 252(4):495-509.
Abstract
Background RERE is a highly conserved transcriptional co-regulator that is associated with a human neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH, OMIM: 616975).
Results We show that the zebrafish rerea mutant (babyface) robustly recapitulates optic fissure closure defects resulting from loss of RERE function, as observed in humans. These defects result from expansion of proximal retinal optic stalk and reduced expression of some of the ventral retinal fate genes due to deregulated shh signaling. Using zebrafish and cell-based assays, we determined that NEDBEH-associated human RERE variants function as hypomorphs in their ability to repress shh signaling and some exhibit abnormal nuclear localization. Inhibiting shh signaling by the shh/gli inhibitor HPI-1 rescues coloboma, confirming our observation that coloboma in rerea mutants is indeed due to deregulation of shh signaling.
Conclusions Zebrafish rerea mutants exhibit optic stalk and optic fissure closure defects. The optic fissure closure defect was rescued by an shh signaling inhibitor, suggesting that this defect could arise due to deregulated shh signaling. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping