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PDCD2 controls hematopoietic stem cell differentiation during development.
- Source :
-
Stem cells and development [Stem Cells Dev] 2013 Jan 01; Vol. 22 (1), pp. 58-72. Date of Electronic Publication: 2012 Aug 16. - Publication Year :
- 2013
-
Abstract
- Programmed cell death 2 (Pdcd2) is a highly conserved protein of undefined function, and is widely expressed in embryonic and adult tissues. The observations that knockout of Pdcd2 in the mouse is embryonic lethal at preimplantation stages, and that in Drosophila, Zfrp8, the ortholog of Pdcd2, is required for normal lymph gland development suggest that Pdcd2 is important for regulating hematopoietic development. Through genetic and functional studies, we investigated pdcd2 function during the zebrafish ontogeny. Knockdown of pdcd2 expression in zebrafish embryos resulted in defects in embryonic hematopoietic development. Loss of pdcd2 function caused increased expression of progenitor markers, and accumulation of erythroid progenitors during primitive hematopoiesis. Additionally, hematopoietic stem cells (HSCs) failed to appear in the aorta-gonad mesonephros, and were not able to terminally differentiate or reconstitute hematopoiesis. Pdcd2 effects on HSC emergence were cell autonomous and P53-independent, and loss of pdcd2 function was associated with mitotic defects and apoptosis. Restoration of runx1 function(s) and modulation of apoptosis through the inhibition of Jak/Stat signaling rescued the hematopoietic and erythroid defects resulting from pdcd2 knockdown. Our studies suggest that pdcd2 plays a critical role in regulating the transcriptional hierarchy controlling hematopoietic lineage determination. Furthermore, the effects of pdcd2 in regulating mitotic cell death may contribute to its role(s) in directing hematopoietic differentiation during development.
- Subjects :
- Animals
Apoptosis
Apoptosis Regulatory Proteins genetics
Apoptosis Regulatory Proteins physiology
Core Binding Factor Alpha 2 Subunit genetics
Core Binding Factor Alpha 2 Subunit metabolism
Embryo, Nonmammalian blood supply
Embryo, Nonmammalian cytology
Embryo, Nonmammalian metabolism
Erythroid Cells metabolism
Erythropoiesis
Gene Expression
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Humans
Mice
Mitosis
Morpholinos genetics
Neovascularization, Physiologic
Organ Specificity
Transcription Factors genetics
Transcription Factors metabolism
Tumor Suppressor Protein p53 metabolism
Zebrafish
Zebrafish Proteins genetics
Zebrafish Proteins physiology
Apoptosis Regulatory Proteins metabolism
Cell Differentiation
Embryonic Development
Hematopoietic Stem Cells physiology
Zebrafish Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-8534
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Stem cells and development
- Publication Type :
- Academic Journal
- Accession number :
- 22800338
- Full Text :
- https://doi.org/10.1089/scd.2012.0074