Kikuchi Tomoko, Kubonishi Shiro, Shibakura Misako, Namba Noriko, Matsui Toshimitsu, Fukui Yoshinori, Tanimoto Mitsune, Katayama Yoshio
Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Biochem Biophys Res Commun. 2008 Feb 29;367(1):90-6. doi: 10.1016/j.bbrc.2007.12.093. Epub 2007 Dec 26.
Dock2 has been shown to be indispensable for chemotaxis of mature lymphocytes as a critical Rac activator. However, the functional expression of Dock2 in immature hematopoietic cells is unclear. In this study, we demonstrate that Dock2 is broadly expressed in bone marrow (BM) hematopoietic compartment, including hematopoietic stem/progenitor cell (HSC/HPC) fraction. Response of Dock2-/- HPCs to CXCL12 in chemotaxis and actin polymerization in vitro was impaired, although alpha4 integrin activation by CXCL12 was not altered. Myelosuppressive stress on HSCs in vivo, such as consecutive 5-FU administration and serial bone marrow transplantation, did not show hematopoietic defect in Dock2-/- mice. Long-term engraftment of transplanted Dock2-/- BM cells was severely impaired in competitive reconstitution. However, this was not intrinsic to HSCs but originated from the defective competition of Dock2-/- lymphoid precursors. These results suggest that Dock2 plays a significant role in BM lymphopoiesis, but is dispensable for HSC engraftment and self-renewal.
Dock2作为一种关键的Rac激活剂，已被证明对成熟淋巴细胞的趋化作用不可或缺。然而，Dock2在未成熟造血细胞中的功能表达尚不清楚。在本研究中，我们证明Dock2在骨髓（BM）造血区广泛表达，包括造血干/祖细胞（HSC/HPC）部分。尽管CXCL12对α4整合素的激活未改变，但Dock2基因敲除的HPCs在体外趋化作用和肌动蛋白聚合中对CXCL12的反应受损。体内对HSCs的骨髓抑制应激，如连续给予5-氟尿嘧啶和连续骨髓移植，在Dock2基因敲除小鼠中未显示造血缺陷。在竞争性重建中，移植的Dock2基因敲除BM细胞的长期植入严重受损。然而，这并非HSCs所固有，而是源于Dock2基因敲除淋巴前体的竞争缺陷。这些结果表明，Dock2在BM淋巴细胞生成中起重要作用，但对HSC植入和自我更新并非必需。
