PUBLICATION

Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish

Authors: Lu, X., Wei, Y., Liu, F.
ID: ZDB-PUB-170214-237
Date: 2015
Source: Cell discovery 1: 15027 (Journal)
Registered Authors: Liu, Feng, Lu, Xinyan, Wei, Yonglong
Keywords: HSCs, HSPCs, miR-142a-3p, p53, survival, Haematopoietic stem cells
MeSH Terms: none
PubMed: 27462426 Full text @ Cell Discov

Abstract

Hematopoietic stem and progenitor cells have the capacity to self-renew and differentiate into all blood cell lineages, and thus sustain life-long homeostasis of the hematopoietic system. Although intensive studies have focused on the orchestrated genetic network of hematopoietic stem and progenitor cell specification and expansion, relatively little is known on the regulation of hematopoietic stem and progenitor cell survival during embryogenesis. Here, we generated two types of miR-142a-3p genetic mutants in zebrafish and showed that the loss-of-function mutants displayed severe reduction of hematopoietic stem and progenitor cells. Further analysis showed that the diminished proliferation and excessive apoptosis in miR-142a-3p mutants were attributed to the increased p53 signaling. Mechanistically, we demonstrated that miR-142a-3p directly targets p53 during hematopoietic stem and progenitor cell development, and the hematopoietic stem and progenitor cell survival defect in miR-142a-3p mutants could be rescued by loss of p53. Therefore, our work reveals the significance of the miR-142a-3p-p53 pathway in controlling hematopoietic stem and progenitor cell survival, and thus advances our understanding of the role of p53 in vertebrate hematopoiesis.

Genes / Markers

Marker	Marker Type	Name
aplnra	GENE	apelin receptor a
casp8	GENE	caspase 8, apoptosis-related cysteine peptidase
cdkn1a	GENE	cyclin dependent kinase inhibitor 1A
dlc	GENE	deltaC
dll4	GENE	delta-like 4 (Drosophila)
efnb2a	GENE	ephrin-B2a
fas	GENE	Fas cell surface death receptor
flt4	GENE	fms related receptor tyrosine kinase 4
gata1a	GENE	GATA binding protein 1a
ikzf1	GENE	IKAROS family zinc finger 1 (Ikaros)

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
cdkn1a	mir142a^ioz13/ioz13	standard conditions	Prim-25	trunk	RTPCR	Fig. 5
cdkn1a	mir142a^ioz13/ioz13	standard conditions	Prim-5	trunk	RTPCR	Fig. 5
EGFP	mir142a^ioz13/ioz13; zf169Tg	standard conditions	Prim-25	hematopoietic multipotent progenitor cell	IHC	Fig. 2
EGFP	zf169Tg	standard conditions	Prim-25	hematopoietic multipotent progenitor cell	IHC	Fig. 2
gata1a	mir142a^ioz13/ioz13	standard conditions	Day 4	caudal hematopoietic tissue hematopoietic multipotent progenitor cell	ISH	Fig. 2
gata1a	mir142a^ioz13/ioz13	standard conditions	Day 4	erythroid lineage cell	ISH	Fig. 2
gata1a	WT	standard conditions	Day 4	caudal hematopoietic tissue hematopoietic multipotent progenitor cell	ISH	Fig. 2
gata1a	WT	standard conditions	Day 4	erythroid lineage cell	ISH	Fig. 2
ikzf1	mir142a^ioz13/ioz13	standard conditions	Day 4	lymphocyte	ISH	Fig. 2
ikzf1	mir142a^ioz13/ioz13	standard conditions	Day 4	thymus	ISH	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
mir142a^ioz13/ioz13	standard conditions	26+ somites	hematopoietic multipotent progenitor cell apoptotic process increased occurrence, abnormal	Fig. 4
mir142a^ioz13/ioz13	standard conditions	Prim-5	hematopoietic multipotent progenitor cell runx1 expression decreased amount, abnormal	Fig. 2
mir142a^ioz13/ioz13	standard conditions	Prim-5	hematopoietic multipotent progenitor cell apoptotic process increased occurrence, abnormal	Fig. 4
mir142a^ioz13/ioz13	standard conditions	Prim-5	hematopoietic multipotent progenitor cell cell population proliferation decreased occurrence, abnormal	Fig. 4
mir142a^ioz13/ioz13	standard conditions	Prim-5	hemopoiesis decreased occurrence, abnormal	Fig. 2
mir142a^ioz13/ioz13	standard conditions	Prim-5	trunk cdkn1a expression increased amount, abnormal	Fig. 5
mir142a^ioz13/ioz13	standard conditions	Prim-5	trunk irf7 expression increased amount, abnormal	Fig. 8
mir142a^ioz13/ioz13	standard conditions	Prim-5	trunk runx1 expression decreased amount, abnormal	Fig. 2
mir142a^ioz13/ioz13	standard conditions	Prim-5	trunk tp53 expression increased amount, abnormal	Fig. 8
mir142a^ioz13/ioz13	standard conditions	Prim-5	trunk tp53 expression increased amount, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ioz13		Small Deletion	mir142a
ioz14		Small Deletion	mir142a
zdf1		Point Mutation	tp53
zf169Tg	TgPAC(myb:2xmyb-EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
irf7	MO1-irf7	MRPHLNO
mir142a	CRISPR1-mir142a	CRISPR
mir142a	CRISPR2-mir142a	CRISPR
mir142a	TALEN1-mir142a	TALEN
tp53	MO4-tp53	MRPHLNO

Fish

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-runx1	polyclonal		IgG	Rabbit
Ab6-myc	polyclonal			Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Lu et al., 2015 ZDB-PUB-170214-237 PMID:27462426

Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish

Lu et al., 2015

ZDB-PUB-170214-237
PMID:27462426