Role of the proto-oncogene Ret during haematopoietic differenciation

• Author(s): Campos, Mariana Rodrigues
• Date: 2009
• Persistent ID: http://hdl.handle.net/10451/1417
• Origin: Repositório da Universidade de Lisboa
• Subject(s): Embriologia; Diferenciação celular; Células estaminais; Teses de mestrado
• Document Type: Master thesis
• Language: English
• Advisor(s): Veiga-Fernandes, Henrique; Sucena, Élio
• Contributor(s): Repositório da Universidade de Lisboa

Description

Tese de mestrado, Biologia (Biologia Evolutiva e do Desenvolvimento), 2009, Universidade de Lisboa, Faculdade de Ciências

Haematopoiesis is a tightly regulated developmental cascade responsible for the generation of all haematopoietic cell types. Many molecules have been involved in this process, namely tyrosine kinase family members. This family includes the tyrosine kinase receptor RET, encoded by a proto-oncogene and classically allocated to nervous system function. Herein we show that Ret and its co-receptors Gfra1 and Gfra2 are highly expressed in haematopoietic stem cells (HSC). Using mice homozygous for a null mutation of Ret we show that ablation of this gene has a major impact in the foetal liver cellularity. Accordingly, the HSC compartment of Ret deficient embryos shows a 2.2 fold reduction when compared to their WT littermate controls. Despite reduced foetal liver cellularity, HSC from Ret null mice display normal differentiation into B lymphocyte, erythroid and myeloid lineages. Conversely, Ret null HSCs have a reduction of quiescent cells, which also correlated with a reduction in long‐term reconstitution haematopoietic stem cells. These findings suggest defects in haematopoietic activity and reconstitution potential. Accordingly, HSCs from Ret-/- origin have a reduction in CFU‐S potential and poorly reconstitute lethally irradiated hosts. In fact, two months after competitive transplantation, cells from Ret null origin represented less than half of the haematopoietic cells in recipient mice, while WT cells already accounted for more than 80% of the haematopoietic pool of the host. Thus RET emerges as a novel molecule in haematopoiesis, supporting the concept that molecular mechanisms historically ascribed to specific tissues can be more widely used in order to orchestrate the function of systems derived from different germ layers

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