PUBLICATION

let-7 MicroRNA-Mediated Regulation of Shh Signaling and the Gene Regulatory Network Is Essential for Retina Regeneration

Authors

Kaur, S., Gupta, S., Chaudhary, M., Khursheed, M.A., Mitra, S., Kurup, A.J., Ramachandran, R.

ID

ZDB-PUB-180503-9

Date

2018

Source

Cell Reports 23: 1409-1423 (Journal)

Registered Authors

Kurup, Akshai Janardhana

Keywords

Ascl1a, Foxn4, Lin28, Mmp9, Shh, Zic2b, let-7, regeneration, retina, zebrafish

Datasets

GEO:GSE102063

MeSH Terms

Retina*/cytology
Retina*/metabolism
Humans
Stem Cells/cytology
Stem Cells/metabolism
Zebrafish/genetics
Zebrafish/metabolism*
Gene Regulatory Networks/physiology*
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Hedgehog Proteins/genetics
Hedgehog Proteins/metabolism*
Animals
Ependymoglial Cells/cytology
Ependymoglial Cells/metabolism
MicroRNAs/genetics
MicroRNAs/metabolism*
Signal Transduction/physiology*
Regeneration/physiology*

(all 19)

PubMed

29719254 Full text @ Cell Rep.

Abstract

Upon injury, Müller glia cells of the zebrafish retina reprogram themselves to progenitor cells with stem cell characteristics. This necessity for retina regeneration is often compromised in mammals. We explored the significance of developmentally inevitable Sonic hedgehog signaling and found its necessity in MG reprogramming during retina regeneration. We report on stringent translational regulation of sonic hedgehog, smoothened, and patched1 by let-7 microRNA, which is regulated by Lin28a, in Müller glia (MG)-derived progenitor cells (MGPCs). We also show Shh-signaling-mediated induction of Ascl1 in mouse and zebrafish retina. Moreover, Shh-signaling-dependent regulation of matrix metalloproteinase9, in turn, regulates Shha levels and genes essential for retina regeneration, such as lin28a, zic2b, and foxn4. These observations were further confirmed through whole-retina RNA-sequencing (RNA-seq) analysis. This mechanistic gene expression network could lead to a better understanding of retina regeneration and, consequently, aid in designing strategies for therapeutic intervention in human retinal diseases.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ascl1a	WT	perforation: retina	Adult	regenerating tissue Muller cell	ISH	Fig. 4
ascl1a	WT	perforation: retina	Adult	regenerating tissue Muller cell	ISH	Fig. 6
ascl1a	WT	perforation: retina	Adult	regenerating tissue Muller cell	ISH	Fig. 2
ascl1a	WT	perforation: retina	Adult	regenerating tissue Muller cell	ISH	Fig. 5
ascl1a	WT	perforation: retina	Adult	regenerating tissue retina	ISH	Fig. 4
ascl1a	WT	perforation: retina, chemical treatment: DAPT	Adult	regenerating tissue retina	RTPCR	Fig. 4
ascl1a	WT	perforation: retina	Adult	regenerating tissue retina	ISH	Fig. 2
ascl1a	WT	perforation: retina, chemical treatment: Cyclopamine	Adult	regenerating tissue retina	RTPCR	Fig. 1
ascl1a	WT	perforation: retina, chemical treatment: Cyclopamine	Adult	regenerating tissue retina	ISH	Fig. 2
ascl1a	WT	perforation: retina	Adult	regenerating tissue retina	RTPCR	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: Cyclopamine	Day 4	eye fused with eye, abnormal	Fig. 1
WT	perforation: retina, chemical treatment: DAPT	Adult	regenerating tissue retina ascl1a expression increased amount, abnormal	Fig. 4
WT	perforation: retina, chemical treatment: DAPT	Adult	regenerating tissue retina mmp9 expression increased amount, abnormal	Fig. 4
WT	perforation: retina, chemical treatment: DAPT	Adult	regenerating tissue retina Ab1-shha labeling increased amount, abnormal	Fig. 4
WT	perforation: retina, chemical treatment: DAPT	Adult	regenerating tissue retina Ab3-ascl1 labeling increased amount, abnormal	Fig. 4
WT	perforation: retina, chemical treatment: Cyclopamine	Adult	Muller cell cell dedifferentiation decreased occurrence, abnormal	Fig. 1
WT	perforation: retina, chemical treatment: Cyclopamine	Adult	regenerating tissue Muller cell decreased amount, abnormal	Fig. 1
WT	perforation: retina, chemical treatment: Cyclopamine	Adult	regenerating tissue retina ascl1a expression decreased amount, abnormal	Fig. 2
WT	perforation: retina, chemical treatment: Cyclopamine	Adult	regenerating tissue retina ascl1a expression decreased amount, abnormal	Fig. 2
WT	perforation: retina, chemical treatment: Cyclopamine	Adult	regenerating tissue retina ascl1a expression decreased amount, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
mi4Tg	Tg(-1.0Cau.Tuba1:GFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ascl1a	MO3-ascl1a	MRPHLNO
foxn4	MO3-foxn4	MRPHLNO
gli1	MO2-gli1	MRPHLNO
gli2a	MO3-gli2a	MRPHLNO
gli3	MO3-gli3	MRPHLNO
lin28ab	MO1-lin28ab	MRPHLNO
mmp9	MO7-mmp9	MRPHLNO
ptch1	MO1-ptch1	MRPHLNO
ptch2	MO4-ptch2	MRPHLNO
shha	MO5-shha	MRPHLNO

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Fish

Fish
mi4Tg
WT
WT + MO1-lin28ab
WT + MO2-gli1
WT + MO2-gli1 + MO3-gli3
WT + MO2-gli1 + MO3-zic2b + MO4-zic2b
WT + MO2-sufu
WT + MO3-ascl1a
WT + MO3-foxn4
WT + MO3-gli3

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Kaur et al., 2018 ZDB-PUB-180503-9 PMID:29719254

let-7 MicroRNA-Mediated Regulation of Shh Signaling and the Gene Regulatory Network Is Essential for Retina Regeneration

Kaur et al., 2018

ZDB-PUB-180503-9
PMID:29719254