Implication of expression of GDNF/Ret signalling components in differentiation of bone marrow haemopoietic cells

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) medi ate their actions through a unique multicomponent receptor system composed of Ret receptor tyrosine kinase and glycosyl-phosphatidylinositol-linked ce ll surface proteins (designated GFR alpha-1 and GFR alpha-2). In the presen t study, expression of these signalling components in the process of differ entiation of haemopoietic cells was investigated. Ret was expressed at vari able levels in normal and malignant cells of the myelomonocyte lineage. Imm unohistochemical analysis of human and mouse tissues revealed that Ret expr ession was increased in intermediate mature rnyeloid cells such as promyelo cytes and myelocytes and decreased in mature granulocytes and monocytes. Co nsistent with this observation, when THP-1 monocytic and HL-60 promyelocyti c leukaemia cells expressing Ret were differentiated toward macrophages or granulocytes by treatment of 12-O-tetradecanoylphorbol-13-acetate (TPA) or all-trans retinoic acid (RA), Ret expression strikingly decreased during di fferentiation. Expression of GDNF, NTN, GFR alpha-1 and GFR alpha-2 was und etectable in THP-1 and HL-60 cells as well as in bone marrow haemopoietic c ells. In contrast, bone marrow stromal cells appeared to express GDNF GFR a lpha-1 and GFR alpha-2 but not Ret. These findings suggested that the inter action between stromal cells and Ret-expressing haemopoietic cells in the b one marrow microenvironment may play a role in the differentiation of myelo monocyte-lineage cells through activation of the GDNF/Ret signalling pathwa y.