PUBLICATION

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Authors

Johansson, J.A., Marie, K.L., Lu, Y., Brombin, A., Santoriello, C., Zeng, Z., Zich, J., Gautier, P., von Kriegsheim, A., Brunsdon, H., Wheeler, A.P., Dreger, M., Houston, D.R., Dooley, C.M., Sims, A.H., Busch-Nentwich, E.M., Zon, L.I., Illingworth, R.S., Patton, E.E.

ID

ZDB-PUB-200712-8

Date

2020

Source

Developmental Cell 54(3): 317-332.e9 (Journal)

Registered Authors

Brombin, Alessandro, Busch-Nentwich, Elisabeth, Dooley, Christopher, Patton, E. Elizabeth, Santoriello, Cristina, Zeng, Zhiqiang, Zon, Leonard I.

Keywords

DDX21, MITF, PRL3, PTP4A3, melanocyte stem cell, melanoma, regeneration, small-molecule screen, transcription elongation, zebrafish

MeSH Terms

Neoplasm Proteins/genetics
Neoplasm Proteins/metabolism*
Stem Cells/metabolism
Animals
Zebrafish/metabolism
Gene Expression Regulation, Developmental
Melanocytes/cytology*
DEAD-box RNA Helicases/genetics
DEAD-box RNA Helicases/metabolism*
Melanoma/genetics
Melanoma/metabolism*
Microphthalmia-Associated Transcription Factor/genetics
Cell Differentiation/genetics*
Protein Tyrosine Phosphatases/genetics
Protein Tyrosine Phosphatases/metabolism*
Humans
Mutation
Zebrafish Proteins/metabolism

(all 18)

PubMed

32652076 Full text @ Dev. Cell

Abstract

Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
DsRed	w47Tg/+; zf148Tg/+	chemical treatment: 2-nitrofuran	Protruding-mouth	peripheral nervous system	IFL	Fig. 2
DsRed	w47Tg/+; zf148Tg/+	chemical treatment: rhodanine	Protruding-mouth	peripheral nervous system	IFL	Fig. 2
DsRed	w47Tg/+; zf148Tg/+	chemical treatment: rhodanine, chemical treatment: 2-nitrofuran	Protruding-mouth	peripheral nervous system	IFL	Fig. 2
DsRed	w47Tg/+; zf148Tg/+	control	Protruding-mouth	peripheral nervous system	IFL	Fig. 2
foxd3	mitfa^vc7/vc7	heat shock	Long-pec	lateral line	ISH	Fig. 2
foxd3	mitfa^vc7/vc7	heat shock, chemical treatment: rhodanine	Long-pec	lateral line	ISH	Fig. 2
GFP	w47Tg/+; zf148Tg/+	chemical treatment: rhodanine	Protruding-mouth	melanoblast	IFL	Fig. 2
GFP	w47Tg/+; zf148Tg/+	chemical treatment: 2-nitrofuran	Protruding-mouth	melanoblast	IFL	Fig. 2
GFP	w47Tg/+; zf148Tg/+	chemical treatment: rhodanine, chemical treatment: 2-nitrofuran	Protruding-mouth	melanoblast	IFL	Fig. 2
GFP	w47Tg/+; zf148Tg/+	control	Protruding-mouth	melanoblast	IFL	Fig. 2

1 - 10 of 17

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: 2-nitrofuran	Long-pec	melanocyte decreased pigmentation, abnormal	Fig. 1
WT	chemical treatment: rhodanine, chemical treatment: 2-nitrofuran	Long-pec	melanocyte decreased pigmentation, abnormal	Fig. 1
mitfa^vc7/vc7	heat shock, chemical treatment: rhodanine	Long-pec	melanocyte mitfa expression increased distribution, abnormal	Fig. 2
mitfa^vc7/vc7	heat shock, chemical treatment: rhodanine	Day 4	melanocyte decreased pigmentation, abnormal	Fig. 1
mitfa^vc7/vc7	heat shock, chemical treatment: rhodanine	Day 4	melanocyte pigmented, ameliorated	Fig. 6
mitfa^vc7/vc7	heat shock, chemical treatment: rhodanine, chemical treatment: concanamycin A	Day 4	melanocyte pigmented, ameliorated	Fig. 6
mitfa^vc7/vc7; ptp4a3a^ue404/ue404	heat shock, chemical treatment: rhodanine	Day 4	melanocyte pigmented, ameliorated	Fig. 6
mitfa^vc7/vc7; ptp4a3a^ue404/ue404	heat shock, chemical treatment: rhodanine	Day 4	melanocyte pigmented, ameliorated	Fig. 1
mitfa^vc7/vc7; ptp4a3a^ue404/ue404	heat shock, chemical treatment: rhodanine, chemical treatment: concanamycin A	Day 4	melanocyte decreased pigmentation, abnormal	Fig. 6
mitfa^vc7/vc7; ptp4a3a^ue404/ue404; ptp4a3b^ue405/ue405	heat shock, chemical treatment: rhodanine	Day 4	melanocyte decreased pigmentation, abnormal	Fig. 1

1 - 10 of 13

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ue403Tg	Tg(actb2:ptp4a3a,myl7:EGFP)	Transgenic Insertion
ue404		Small Deletion	ptp4a3a
ue405		Small Deletion	ptp4a3b
vc7		Point Mutation	mitfa
w47Tg	Tg(mitfa:GFP)	Transgenic Insertion
zf148Tg	Tg(Xla.Tubb:DsRed)	Transgenic Insertion

1 - 6 of 6

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ddx21	MO1-ddx21	MRPHLNO
ptp4a3a	MO1-ptp4a3a	MRPHLNO
ptp4a3a	TALEN1-ptp4a3a	TALEN
ptp4a3b	CRISPR1-ptp4a3b	CRISPR
ptp4a3b	MO1-ptp4a3b	MRPHLNO

Fish

Fish
mitfa^vc7/vc7
mitfa^vc7/vc7; ptp4a3a^ue404/ue404
mitfa^vc7/vc7; ptp4a3a^ue404/ue404; ptp4a3b^ue405/ue405
mitfa^vc7/vc7; ue403Tg/+
w47Tg/+; zf148Tg/+
WT

Antibodies

Name	Type	Isotypes	Host Organism
Ab1-ddx21	monoclonal	IgG	Rabbit
Ab1-ptp4a3	monoclonal	IgG1	Mouse
Ab2-ddx21	monoclonal	IgG1	Mouse
Ab2-mitf	polyclonal	IgG	Rabbit
Ab3-ddx21	polyclonal	IgG	Rabbit

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Johansson et al., 2020 ZDB-PUB-200712-8 PMID:32652076

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Johansson et al., 2020

ZDB-PUB-200712-8
PMID:32652076