Abstract
BackgroundLoss of the tumor suppressor phosphatase and tensin homolog (PTEN) is frequently observed in hematopoietic malignancies. Although PTEN has been implicated in maintaining the quiescence of hematopoietic stem cells (HSCs), its role in hematopoiesis during ontogeny remains largely unexplored.MethodsThe expression of hematopoietic marker genes was analyzed via whole mount in situ hybridization assay in ptena and ptenb double mutant zebrafish. The embryonic myelopoiesis was characterized by living imaging and whole mount in situ immunofluorescence with confocal microscopy, as well as cell-specific chemical staining for neutrophils and macrophages. Analyses of the involved signaling pathway were carried out by inhibitor treatment and mRNA injection.ResultsPten-deficient zebrafish embryos exhibited a strikingly increased number of myeloid cells, which were further characterized as being immune deficient. In accordance with this finding, the inhibition of phosphoinositide 3-kinase (PI3K) or the mechanistic target of rapamycin (mTOR) corrected the expansive myelopoiesis in the pten-deficient embryos. Further mechanistic studies revealed that the expression of cebpa, a critical transcription factor in myeloid precursor cells, was downregulated in the pten-deficient myeloid cells, whereas the injection of cebpa mRNA markedly ameliorated the dysmyelopoiesis induced by the loss of pten.ConclusionsOur data provide in vivo evidence that definitive myelopoiesis in zebrafish is critically regulated by pten via the elevation of cebpa expression.
Highlights
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is frequently observed in hematopoietic malignancies
Loss of pten induces abnormal hematopoiesis in zebrafish larvae To evaluate the role of pten in hematopoiesis, we examined the expression of critical hematopoietic genes in pten-deficient zebrafish by using whole-mount in situ hybridization analysis
We examined the hematopoietic phenotypes in ptena and ptenb double-mutant embryos, which were derived from an incross of ptena+/−ptenb−/− zebrafish
Summary
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is frequently observed in hematopoietic malignancies. PTEN has been implicated in maintaining the quiescence of hematopoietic stem cells (HSCs), its role in hematopoiesis during ontogeny remains largely unexplored. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a well-characterized tumor suppressor gene, and PTEN deficiency is frequently observed in various types of cancers, including brain cancer, breast cancer, prostate cancer, endometrial carcinoma, melanoma, and leukemia. Conditional ablation of Pten in the hematopoietic stem cells (HSCs) of adult mice leads to rapid HSC depletion and the formation of leukemia-initiating cells (LICs) [6,7]. A recent study further showed that the mechanistic target of rapamycin (mTOR) activation upon Pten deletion is critical during rapid HSC depletion [8]. MTOR complex 1 (mTORC1) is required to sustain normal hematopoiesis [9,10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
