Comparative hematopoiesis and signal transduction in model organisms

Gautam, Dushyant Kumar; Chimata, Anuradha Venkatakrishnan; Gutti, Ravi Kumar; Paddibhatla, Indira

doi:10.1002/jcp.30287

“…25,77 These HSPCs enter into the circulation and target CHT along arteries within 48-hpf, thymus by 3 days post-fertilization, and kidney marrow by 4 days post-fertilization as prime hematopoietic organs for embryonic hematopoiesis. 25,78 Lam et al 79 used runx1P2 :EGFP transgenic zebra fish to show that during adult hematopoiesis, EGFP-labeled HSPCs were localized to the larval thymus and larval, juvenile, and adult kidneys. Using a photoactivatable cell tracer, Bertrand et al 80 showed that DA-originated HSPCs migrated through blood to seed in the CHT region of the tail and then differentiated, expanded, matured, and migrated to the thymus and kidney.…”

Section: Discussionmentioning

confidence: 99%

Aggf1 Specifies Hemangioblasts at the Top of Regulatory Hierarchy via Npas4l and mTOR-S6K-Emp2-ERK Signaling

Yang,

Guo,

Zhao

et al. 2023

ATVB

2

0

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BACKGROUND: Hemangioblasts are mesoderm-derived multipotent stem cells for differentiation of all hematopoietic and endothelial cells in the circulation system. However, the underlying molecular mechanism is poorly understood. METHODS: CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 editing was used to develop aggf1 −/− and emp2 −/− knockout zebra fish. Whole-mount in situ hybridization and transgenic Tg( gata1 -EGFP), Tg( mpx -EGFP), Tg( rag2 -DsRed), Tg( cd41 -EGFP), Tg( kdrl -EGFP), and Tg( aggf1 −/− ; kdrl -EGFP) zebra fish were used to examine specification of hemangioblasts and hematopoietic stem and progenitor cells (HSPCs), hematopoiesis, and vascular development. Quantitative real-time polymerase chain reaction and Western blot analyses were used for expression analysis of genes and proteins. RESULTS: Knockout of aggf1 impaired specification of hemangioblasts and HSPCs, hematopoiesis, and vascular development in zebra fish. Expression of npas4l / cloche —the presumed earliest marker for hemangioblast specification—was significantly reduced in aggf1 −/− embryos and increased by overexpression of aggf1 in embryos. Overexpression of npas4l rescued the impaired specification of hemangioblasts and HSPCs and development of hematopoiesis and intersegmental vessels in aggf1 −/− embryos, placing aggf1 upstream of npas4l in hemangioblast specification. To identify the underlying molecular mechanism, we identified emp2 as a key aggf1 downstream gene. Similar to aggf1 , emp2 knockout impaired the specification of hemangioblasts and HSPCs, hematopoiesis, and angiogenesis by increasing the phosphorylation of ERK1/2 (extracellular signal-regulated protein kinase 1/2). Mechanistic studies showed that aggf1 knockdown and knockout significantly decreased the phosphorylated levels of mTOR (mammalian target of rapamycin) and p70 S6K (ribosomal protein S6 kinase), resulting in reduced protein synthesis of Emp2 (epithelial membrane protein 2), whereas mTOR activator MHY1485 rescued the impaired specification of hemangioblasts and HSPCs and development of hematopoiesis and intersegmental vessels and reduced Emp2 expression induced by aggf1 knockdown. CONCLUSIONS: These results indicate that aggf1 acts at the top of npas4l and becomes the earliest marker during specification of hemangioblasts. Our data identify a novel signaling axis of Aggf1 (angiogenic factor with G-patch and FHA domain 1)-mTOR-S6K-ERK1/2 for specification of hemangioblasts and HSPCs, primitive and definitive hematopoiesis, and vascular development. Our findings provide important insights into specification of hemangioblasts and HSPCs essential for the development of the circulation system.

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“…Additionally, the regulatory network of erythropoiesis is highly conserved between zebrafish and humans [ 40 ]. For instance, homologs of almost all transcription factors with important roles in mammalian erythropoiesis are present in zebrafish [ 41 ]. Due to the high conservation of erythropoiesis in vertebrates, mutations in erythropoietic genes commonly lead to similar phenotypes in zebrafish and humans [ 42 ].…”

Section: Zebrafish Erythropoiesismentioning

confidence: 99%

“…In addition, erythropoiesis is regulated by recruiter lncRNAs, including LncHSC-2, lincRNA-EPS, and alncRNA-EC7/Bloodlinc, and decoy lncRNAs, including lnc-DC and lnc-MC [ 51 ]. For more detailed pathways and mechanisms regulating vertebrate erythropoiesis, please refer to the previous reviews [ 1 , 41 , 52 , 53 ]. In this section, we summarize recent progress on the regulation of erythropoiesis with emphasis on the studies in zebrafish.…”

Section: Using Zebrafish To Study the Regulation Of Erythropoiesismentioning

confidence: 99%

Using the Zebrafish as a Genetic Model to Study Erythropoiesis

Zhang

¹

,

Chen

²

,

Chen

³

2021

IJMS

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Vertebrates generate mature red blood cells (RBCs) via a highly regulated, multistep process called erythropoiesis. Erythropoiesis involves synthesis of heme and hemoglobin, clearance of the nuclei and other organelles, and remodeling of the plasma membrane, and these processes are exquisitely coordinated by specific regulatory factors including transcriptional factors and signaling molecules. Defects in erythropoiesis can lead to blood disorders such as congenital dyserythropoietic anemias, Diamond–Blackfan anemias, sideroblastic anemias, myelodysplastic syndrome, and porphyria. The molecular mechanisms of erythropoiesis are highly conserved between fish and mammals, and the zebrafish (Danio rerio) has provided a powerful genetic model for studying erythropoiesis. Studies in zebrafish have yielded important insights into RBC development and established a number of models for human blood diseases. Here, we focus on latest discoveries of the molecular processes and mechanisms regulating zebrafish erythropoiesis and summarize newly established zebrafish models of human anemias.

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“…Hematopoiesis refers to the dynamic and complex process whereby hematopoietic stem cells (HSCs) in hematopoietic tissues form and release different types of blood cells [1] . Generally, vertebrate hematopoiesis occurs in two successive waves, primitive and definitive, that differ in cell types produced and anatomic location.…”

Section: Introductionmentioning

confidence: 99%