Función de la vía de señalización Notch en el desarrollo del sistema hematopoyético

• Autores: Pedro Melgar Rojas
• Directores de la Tesis: José Luis de la Pompa Mínguez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2009
• Idioma: español
• Tribunal Calificador de la Tesis: Ramón Muñoz Chápuli (presid.), María Luisa Toribio García (secret.), Domingo F. Barber Castaño (voc.), Fernando Giráldez Orgaz (voc.), Ignacio Moreno Alborán (voc.)
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Notch is a local signaling pathway that regulates embryonic cell fate determina2on, differen2a2on, and paperning. Vertebrate Notch genes encode an evolu2onarily conserved group of type I transmembrane protein receptors. The extracellular region of Notch can interact with membrane¿bound ligands of the Delta or Serrate/Jagged families in mammals. This interac2on is followed by two sequen2al proteoly2c events that result in the genera2on and nuclear transloca2on of the Notch intracellular domain (NICD). In the nucleus, the NICD heterodimerizes with the transcrip2onal repressor CSL ¿RBPJK in mammals¿ and converts it into a transcrip2onal ac2vator. Main NICD/RBPJk target genes include those encoding basic helix¿loop¿helix (bHLH) transcrip2on factors of the HES and Hey/HRT/Herp families.

    For more than a century, many inves2gators have worked to understand the gene2c regula2on of the hematopoie2c development. In the last two decades, several groups have reported essential func2ons of Notch in defini2ve hematopoiesis and also in binary cell choices along lymphohematopoie2c differen2a2on, specially in T cells. This way, 50% of T¿cell Acute Lymphoblas2c Leukemia (T¿ALL) pa2ents carry transloca2ons and/or muta2ons that result in the cons2tu2ve ac2va2on of Notch1. These data suggest that Notch func2on is essen2al for the correct func2oning of the hematopoie2c system.

    We have examined the effect of overexpression of N1ICD on embryonic Tie2+ cells and their progeny during embryonic development. In the postgastrula2on mouse embryo, Tie2 is expressed in both endothelial and hematopoie2c progenitors. Embryonic day (E) 9 to 10 transgenic embryos (Tie2¿CRE/+;N1ICD/+) showed drama2c reduc2on of embryo¿derived hematopoiesis and hematopoie2c changes in the yolk sac: marked deple2on of mul2potent progenitors, early par2al blockade in erythroid cell differen2a2on and hemoglobiniza2on, and promo2on of the first stages of myelopoiesis, but repression of final matura2on where the genera2on of granulocytes is selec2vely inhibited. In addi2on, the embryonic bipoten2al progenitor popula2on that usually disappears at E7.5¿8, persists un2l E9.5¿10 as an autonomous effect of the overexpression of N1ICD. The intraembryonic defini2ve hematopoiesis is almost completely abolished. Hierarchical gene2c analysis of N1ICD+ vs. WT cell popula2ons revealed that Notch regulates the transcrip2onal ac2vity of genes that are essen2al for the onset, commitment and differen2a2on of hematopoie2c lineages. Taken together with defects in heart development, results in a lethal phenotype between E10¿10.5.

    In summary, our data show that Notch is essen2al during the first stages of embryonic hematopoie2c development may be by ac2ng together with other signalling pathways to regulate the gene expression of target key genes during the embryonic hematopoiesis.