Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling

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...

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Bibliographic Details
Published in:Developmental dynamics 2023-04, Vol.252 (4), p.495-509
Main Authors: George, Aman, Lee, Jerry, Liu, James, Kim, Suzie, Brooks, Brian P.
Format: Article
Language:English
Subjects:
Animals
Anomalies
Carrier Proteins - metabolism
coloboma
Coloboma - genetics
Coloboma - metabolism
Danio rerio
Defects
Deregulation
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
Humans
Inhibitors
Localization
Mutants
Neurodevelopmental disorders
optic fissure
Optic stalk
Proteins
RERE and SHH
Retina
Retina - metabolism
Signal Transduction - physiology
Signaling
Zebrafish
Zebrafish - genetics
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
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Summary: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 (OS) and reduced expression of some of the ventral retinal fate genes due to deregulated protein 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 protein 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 OS 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. Key Findings RERE Coloboma Optic stalk
ISSN:1058-8388
1097-0177
1097-0177
DOI:10.1002/dvdy.561