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Development of Blood Cells in Fish: Transcriptional Factors and Hematopoietic Tissue Specification

Explore the early hematopoietic processes in fish embryos, focusing on transcriptional factors like gata1/2 and lmo2. Discover the intricacies of myelopoiesis, hemogenic sites, and the critical bone marrow niche for hematopoiesis. Uncover the role of Runx1 in 'definitive' hematopoiesis and the transcriptional factors involved in blood cell development. Delve into the implications of disorders like acute lymphoid and chronic myeloid leukemia on hematopoiesis.

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Development of Blood Cells in Fish: Transcriptional Factors and Hematopoietic Tissue Specification

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  1. 5. DEVELOPMENT OF BLOOD

  2. Blood cells Mesonephric tubules

  3. primitive hematopoiesis ventral mesoderm Fish gastrulation movie

  4. scl, gata1/2, lmo2 - transcriptional factors that specify early hematopoietic tissue (gata2 expressed also in ectoderm)RBI – rostral blood islandsICM – inner cell mass gata1 promoter-driven GFP = early erythroid lineage dorsal aorta 5-somitestage embryo – hematopoiesis starts officially ICM 8h embryo 2d embryo circulation

  5. MYELOPOIESIS STARTS IN RBI @ 10-SOMITE STAGEspi1 – marker of myeloid lineage rostral spi1 detected by Fast Red riboprobe scl – early hematovascular cell fatefli1 – early vascular fatenkx2.5 – heart fate caudal

  6. 7.5 dpc mouse embryo (late gastrulation stage) 8.5 dpc – yolk sac encloses entire embryoblood islands merge to form vascular channels LacZ driven by b-globin promoter(X-gal staining – primitive erythroblasts) bl- blood islandsec - ectoplacental coneac - amniotic cavityte - trophectodermal - allantoiseem - extraembryonic mesoderm (blue)ve - visceral endoderme - embryonic ectoderm

  7. AORTA-GONAD MESONEPHROS (AGM) Development of intra-embryonic hemogenic site RUNX1 riboprobe lateral plate mesoderm hemogenic site fetal liver ICM A aorta HSC Rohon-Beard neurons A- aortaNO- notochordAV- axial veine - endothelial cell

  8. RUNX1 (CBFA2, AML1) is necessary for ‘definitive’ hematopoiesis to start at AGM Runx1+/- Runx1-/- E11.5: dark- hematopoietic cells only a few primitive erythrocytes left – likely a carry-over from the ‘primitive’ hematopoiesis

  9. EXTRAEMBRYONAL vs EMBRYONAL PRIMITIVE vs. DEFINITIVE

  10. BONE MARROW NICHE IS CRITICAL FOR HEMATOPOIESIS

  11. COLLAGEN TYPE-X DELETION Col X-/- wt wt Col X-/- thymus spleen wt Col X-/- aplasia normal hematopoiesis

  12. THE HUNT FOR HEMANGIOBLAST AND ITS HEM- ANGIO-DIFFERENTIATION

  13. HEMANGIOBLASTscattered among endothelial and HSC in heart field of the gastrula ventral marginal cells of the heart field, n- notochord

  14. Endothelial progenitor HEMANGIOBLAST or HAEMOGENIC EPITHELIA, or BOTH?

  15. blast colony-forming cell

  16. Hemangioblast culture tight adherent structure Angiopoietin 1 rec. Integrin alpha 2B

  17. Tie2hic-KIT+CD41_ can generate hematopoietic precursors endothelia in matrigel endothelial markers Tie2hic-KIT+CD41_ are present in vivo by FACS Tie2hic-KIT+CD41_ are present in vivo by IHC

  18. Runx1-/- Blast movies 3, 4Runx-/- movie

  19. TRANSCRIPTIONAL FACTORS IN BLOOD DEVELOPMENT

  20. GATA-1 - binds DNA via a zinc finger motif Dracula fish – loss-of-function mutation in GATA1 – impaired erythroid differentiation

  21. Spadetail/TBX16DNA binding domain derived from the prototype gene called transcription factor T impaired erythroid but not myelopoietic differentiation

  22. MoonshineTIM-family of transcriptional factors erythrocyte proerythroblast ‘primitive’ – survival of HSC ‘definitive’ – cardiomegaly and impaired red cell differentiation

  23. WHEN SOMETHING GOES WRONG WITH BLOOD

  24. ACUTE LYMPHOID LEUKEMIA

  25. CHRONIC MYELOID LEUKEMIA abl bcr-abl bcr mice transplanted with patient bone marrow

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