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6 . DEVELOPMENT OF BLOOD

This comprehensive study delves into blood development, focusing on transcriptional factors like gata1/2 and lmo2. It covers various stages from primitive to definitive hematopoiesis, detailing the roles of regulatory genes in different tissues. Using examples from fish to mice, the text highlights critical sites like RBI, ICM, and AGM involved in hematopoiesis. Moreover, it discusses the development of blood islands, intra-embryonic hemogenic sites, and the bone marrow niche, shedding light on the intricate process of hematopoietic cell differentiation. The study also touches upon the role of key transcription factors such as GATA-1 and Spadetail/TBX16 in erythroid differentiation, emphasizing their importance in blood cell formation. Lastly, it examines blood disorders like Chronic Myeloid Leukemia and potential treatments, including the impact of genetic mutations on hematopoietic differentiation.

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6 . DEVELOPMENT OF BLOOD

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  1. 6. DEVELOPMENT OF BLOOD

  2. KRVETVORNAHLAVOLEDVINA 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-/- 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 QUEST FOR A HOLY HEMANGIOBLAST

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

  14. TRANSCRIPTIONAL FACTORS IN BLOOD DEVELOPMENT

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

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

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

  18. WHEN SOMETHING GOES TERRIBLY WRONG WITH BLOOD

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

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