PUBLICATION

Ubiquitin-mediated proteasome degradation regulates optic fissure fusion

Authors: Pereira Piedade, W., Veith, S., Famulski, J.K.
ID: ZDB-PUB-190614-5
Date: 2019
Source: Biology Open 8(6): (Journal)
Registered Authors
Keywords: Coloboma, Nlz2, Optic fissure, Pax2, Proteasome, Retina, SIAH
MeSH Terms: none
PubMed: 31189662 Full text @ Biol. Open

Abstract

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.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: Cyclopamine	Prim-5	central nervous system siah1 expression decreased amount, abnormal	Fig. 3.
AB	chemical treatment by environment: Cyclopamine	Prim-5	whole organism pax2a expression decreased amount, abnormal	Fig. 3.
AB	chemical treatment by environment: Cyclopamine	Prim-5	whole organism siah1 expression decreased amount, abnormal	Fig. 3.
AB	chemical treatment by environment: DMH1	Prim-5	central nervous system pax2a expression increased amount, abnormal	Fig. 3.
AB	chemical treatment by environment: purmorphamine	Prim-5	central nervous system siah1 expression increased amount, abnormal	Fig. 3.
AB	chemical treatment by environment: purmorphamine	Prim-5	whole organism pax2a expression increased amount, abnormal	Fig. 3.
AB	chemical treatment by environment: purmorphamine	Prim-5	whole organism siah1 expression increased amount, abnormal	Fig. 3.
smo^{hi1640Tg/hi1640Tg}	control	Prim-5	whole organism pax2a expression decreased amount, abnormal	Fig. 3.
smo^{hi1640Tg/hi1640Tg}	control	Prim-5	whole organism siah1 expression decreased amount, abnormal	Fig. 3.
smo^{hi1640Tg/hi1640Tg}	standard conditions	Prim-5	central nervous system siah1 expression decreased amount, abnormal	Fig. 3.

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hi1640Tg	Tg(nLacz-GTvirus)	Transgenic Insertion	smo
ua1013Tg	Tg(Ola.Rx3:EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
smo^{hi1640Tg/hi1640Tg}

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Pereira Piedade et al., 2019 ZDB-PUB-190614-5 PMID:31189662

Ubiquitin-mediated proteasome degradation regulates optic fissure fusion

Pereira Piedade et al., 2019

ZDB-PUB-190614-5
PMID:31189662