PUBLICATION

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

Authors

Yakulov, T.A., Todkar, A.P., Slanchev, K., Wiegel, J., Bona, A., Groß, M., Scholz, A., Hess, I., Wurditsch, A., Grahammer, F., Huber, T.B., Lecaudey, V., Bork, T., Hochrein, J., Boerries, M., Leenders, J., de Tullio, P., Jouret, F., Kramer-Zucker, A., Walz, G.

ID

ZDB-PUB-180913-13

Date

2018

Source

Nature communications 9: 3660 (Journal)

Registered Authors

Hess, Isabell, Kramer-Zucker, Albrecht, Lecaudey, Virginie, Slanchev, Krasimir

Keywords

none

MeSH Terms

Animals
Animals, Genetically Modified
Cell Movement
Chemokine CXCL12/metabolism*
Energy Metabolism
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Developmental*
Glycolysis
Homeostasis
Kidney/injuries
Kidney/metabolism
Kidney Diseases/metabolism*
Male
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins/metabolism*
Signal Transduction
Tretinoin/chemistry
Zebrafish/genetics*
Zebrafish Proteins/metabolism*

(all 21)

PubMed

30202007 Full text @ Nat. Commun.

Abstract

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.

Genes / Markers

Marker	Marker Type	Name
ackr3b	GENE	atypical chemokine receptor 3b
cdh17	GENE	cadherin 17, LI cadherin (liver-intestine)
celsr1a	GENE	cadherin EGF LAG seven-pass G-type receptor 1a
cxcl12a	GENE	chemokine (C-X-C motif) ligand 12a (stromal cell-derived factor 1)
cxcr4b	GENE	chemokine (C-X-C motif), receptor 4b
dkk1b	GENE	dickkopf WNT signaling pathway inhibitor 1b
ift88	GENE	intraflagellar transport 88 homolog
myca	GENE	MYC proto-oncogene, bHLH transcription factor a
tp53	GENE	tumor protein p53

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
cdh17	WT	light ablation: pronephros	Long-pec	pronephros	ISH	Fig. 1
cxcr4b	WT	light ablation: pronephros	Long-pec	corpuscles of Stannius	ISH	Fig. 5
cxcr4b	WT	light ablation: pronephros	Long-pec	lateral line	ISH	Fig. 5
cxcr4b	WT	light ablation: pronephros	Long-pec	pronephros	ISH	Fig. 5
EGFP	fu13Tg; zf106Tg	control	Long-pec	pronephric duct membrane	IFL	Fig. 3
EGFP	uf1Tg; zf512Tg	light ablation: pronephros	Long-pec	pronephros	IFL	Fig. 5
EGFP	zf106Tg	light ablation: pronephros	Prim-15	pronephros	IFL	Fig. 1
EGFP	zf106Tg	light ablation: pronephros	Long-pec	pronephros	IHC	Fig. 1
EGFP	zf106Tg	light ablation: pronephros	Prim-5	pronephros	IHC	Fig. 1
myca	WT	control	Prim-5	cloaca	ISH	Fig. S7

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	light ablation: pronephros	Long-pec	pronephros cxcr4b expression increased amount, abnormal	Fig. 5
WT	light ablation: pronephros	Long-pec	pronephros myca expression increased amount, abnormal	Fig. S7
WT + MO2-myca	light ablation: pronephros	Long-pec	pronephros regeneration decreased efficacy, abnormal	Fig. S8
cxcl12a^{t30516/t30516}; fu13Tg; zf106Tg	control	Prim-25	pronephros cell migration process quality, normal	Fig. 3
cxcl12a^{t30516/t30516}; fu13Tg; zf106Tg	control	High-pec	pronephros cell migration process quality, normal	Fig. 3
cxcl12a^{t30516/t30516}; fu13Tg; zf106Tg	control	Long-pec	pronephros cell migration process quality, normal	Fig. 3
cxcl12a^{t30516/t30516}; zf106Tg	light ablation: pronephros	Long-pec	pronephros regeneration decreased efficacy, abnormal	Fig. 4
cxcl12a^{t30516/t30516}; zf106Tg	light ablation: pronephros	Long-pec	pronephros regeneration process quality, abnormal	Fig. 4
cxcr4b^{t26035/t26035}; fu13Tg; zf106Tg	control	Prim-25	pronephros cell migration process quality, normal	Fig. 3
cxcr4b^{t26035/t26035}; fu13Tg; zf106Tg	control	High-pec	pronephros cell migration process quality, normal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
fu13Tg	TgBAC(cxcr4b:Hsa.HIST1H2BJ-RFP)	Transgenic Insertion
li1Tg	Tg(wt1b:EGFP)	Transgenic Insertion
sa16		Point Mutation	ackr3b
t26035		Point Mutation	cxcr4b
t30516		Point Mutation	cxcl12a
tz288		Point Mutation	ift88
uf1Tg	Tg6(cdh17:EGFP)	Transgenic Insertion
uf2		Small Deletion	myca
w32Tg	Tg(hsp70l:dkk1b-GFP)	Transgenic Insertion
zf106Tg	Tg(-8.0cldnb:LY-EGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
celsr1a	MO1-celsr1a	MRPHLNO
myca	CRISPR1-myca	CRISPR
myca	MO1-myca	MRPHLNO
myca	MO2-myca	MRPHLNO
tp53	MO4-tp53	MRPHLNO

Fish

Fish
cxcl12a^{t30516/t30516}; fu13Tg; zf106Tg
cxcl12a^{t30516/t30516}; zf106Tg
cxcr4b^{t26035/t26035}; fu13Tg; zf106Tg
cxcr4b^{t26035/t26035}; zf106Tg
fu13Tg; zf106Tg
myca^uf2/uf2
uf1Tg
uf1Tg; zf512Tg
uf1Tg; zf2017Tg
WT

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
ECFP	EFG	ECFP
EGFP	EFG	EGFP
GFP	EFG	GFP
RFP	EFG	RFP
TagRFP	EFG	TagRFP

Mapping

Yakulov et al., 2018 ZDB-PUB-180913-13 PMID:30202007

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

Yakulov et al., 2018

ZDB-PUB-180913-13
PMID:30202007