PUBLICATION

The Warburg Effect and lactate signaling augment Fgf-MAPK to promote sensory-neural development in the otic vesicle

Authors

Kantarci, H., Gou, Y., Riley, B.B.

ID

ZDB-PUB-200428-2

Date

2020

Source

eLIFE 9: (Journal)

Registered Authors

Riley, Bruce

Keywords

developmental biology, zebrafish

MeSH Terms

Animals
Embryo, Nonmammalian/drug effects
Embryo, Nonmammalian/physiology
Embryonic Development/drug effects
Fibroblast Growth Factors/metabolism*
Gene Expression Regulation, Developmental
Gene Knockout Techniques
Hair Cells, Auditory/physiology
Lactic Acid/metabolism*
Lactic Acid/pharmacology
Mitogen-Activated Protein Kinases/metabolism*
Neurogenesis/drug effects*
Neurons/physiology
Phosphoglycerate Kinase/genetics
Receptors, Fibroblast Growth Factor
Reverse Genetics
Signal Transduction
Zebrafish/genetics
Zebrafish/physiology*
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism

(all 21)

PubMed

32338604 Full text @ Elife

Abstract

Recent studies indicate that many developing tissues modify glycolysis to favor lactate synthesis, but how this promotes development is unclear. Using forward and reverse genetics in zebrafish, we show that disrupting the glycolytic gene phosphoglycerate kinase-1 (pgk1) impairs Fgf-dependent development of hair cells and neurons in the otic vesicle and other neurons in the CNS/PNS. Fgf-MAPK signaling underperforms in pgk1-/- mutants even when Fgf is transiently overexpressed. Wild-type embryos treated with drugs that block synthesis or secretion of lactate mimic the pgk1-/- phenotype, whereas pgk1-/- mutants are rescued by treatment with exogenous lactate. Lactate treatment of wild-type embryos elevates expression of Etv5b/Erm even when Fgf signaling is blocked. However, lactate's ability to stimulate neurogenesis is reversed by blocking MAPK. Thus, lactate raises basal levels of MAPK and Etv5b (a critical effector of the Fgf pathway), rendering cells more responsive to dynamic changes in Fgf signaling required by many developing tissues.

Genes / Markers

Marker	Marker Type	Name
atoh1a	GENE	atonal bHLH transcription factor 1a
dlx3b	GENE	distal-less homeobox 3b
etv5b	GENE	ETS variant transcription factor 5b
fgf3	GENE	fibroblast growth factor 3
fgf8a	GENE	fibroblast growth factor 8a
fgfr1a	GENE	fibroblast growth factor receptor 1a
hsp70l	GENE	heat shock cognate 70-kd protein, like
neurod1	GENE	neuronal differentiation 1
neurog1	GENE	neurogenin 1
otx1	GENE	orthodenticle homeobox 1

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atoh1a	AB	control	Prim-15	anterior macula	ISH	Figure 2
atoh1a	AB	control	Prim-5	anterior macula	ISH	Figure 2
atoh1a	AB	control	Prim-5	posterior macula	ISH	Figure 2
atoh1a	AB	control	Prim-15	posterior macula	ISH	Figure 2
atoh1a	pgk1^x40/x40	control	Prim-5	anterior macula	ISH	Figure 2
atoh1a	pgk1^x40/x40	control	Prim-15	anterior macula	ISH	Figure 2
atoh1a	pgk1^x40/x40	control	Prim-15	posterior macula	ISH	Figure 2
atoh1a	pgk1^x40/x40	control	Prim-5	posterior macula	ISH	Figure 2
dlx3b	AB	control	Prim-15	otic vesicle dorsal region	ISH	Figure 2
dlx3b	pgk1^x40/x40	control	Prim-15	otic vesicle dorsal region	ISH	Figure 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: 2-deoxy-D-glucose	Prim-5	otic vesicle neurog1 expression decreased amount, abnormal	Figure 6
AB	chemical treatment by environment: alpha-cyano-4-hydroxycinnamic acid	14-19 somites	otic vesicle etv5b expression decreased amount, abnormal	Figure 6
AB	chemical treatment by environment: alpha-cyano-4-hydroxycinnamic acid	Prim-5	otic vesicle neurog1 expression decreased amount, abnormal	Figure 6
AB	chemical treatment by environment: alpha-cyano-4-hydroxycinnamic acid, chemical treatment by environment: lactate	14-19 somites	otic vesicle etv5b expression amount, ameliorated	Figure 6
AB	chemical treatment by environment: ATP, chemical treatment by environment: enzyme inhibitor	Prim-5	otic vesicle neurog1 expression decreased amount, abnormal	Figure 6
AB	chemical treatment by environment: enzyme inhibitor	14-19 somites	otic vesicle etv5b expression decreased amount, abnormal	Figure 6
AB	chemical treatment by environment: enzyme inhibitor	Prim-5	otic vesicle neurog1 expression decreased amount, abnormal	Figure 6
AB	chemical treatment by environment: enzyme inhibitor, chemical treatment by environment: lactate	14-19 somites	otic vesicle etv5b expression amount, ameliorated	Figure 6
AB	chemical treatment by environment: enzyme inhibitor, chemical treatment by environment: lactate	Prim-5	otic vesicle neurog1 expression amount, ameliorated	Figure 6
AB	chemical treatment by environment: lactate	14-19 somites	otic vesicle etv5b expression increased amount, abnormal	Figure 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
pd1Tg	Tg(hsp70l:dnfgfr1a-EGFP)	Transgenic Insertion
s356tTg	Tg(pou4f3:GAP-GFP)	Transgenic Insertion
x17Tg	Tg1(hsp70l:fgf8a)	Transgenic Insertion
x40		Complex	pgk1
x55		Indel	pgk1
x65Tg	Tg(hsp70l:pgk1)	Transgenic Insertion
x66Tg	Tg2(hsp70l:pgk1)	Transgenic Insertion
zc7Tg	Tg(-17.6isl2b:GFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
pgk1	CRISPR2-pgk1	CRISPR
pgk1	MO2-pgk1	MRPHLNO
pgk1	MO3-pgk1	MRPHLNO
pgk1	MO4-pgk1	MRPHLNO
plg	MO1-plg	MRPHLNO
plg	MO2-plg	MRPHLNO
tp53	MO4-tp53	MRPHLNO

Fish

Fish
AB
pd1Tg
pgk1^x40/x40
pgk1^x40/x40; s356tTg
pgk1^x40/x40; x65Tg; zc7Tg
pgk1^x40/x40; zc7Tg
pgk1^x40/x40; zc7Tg + MO1-plg + MO4-tp53
pgk1^x55/x55
pgk1^x55/x55; x17Tg
pgk1^x55/x55; x66Tg; zc7Tg

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab2-isl	monoclonal	isl1a isl2a	IgG2b	Mouse

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Kantarci et al., 2020 ZDB-PUB-200428-2 PMID:32338604

The Warburg Effect and lactate signaling augment Fgf-MAPK to promote sensory-neural development in the otic vesicle

Kantarci et al., 2020

ZDB-PUB-200428-2
PMID:32338604