Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
The Jackson Laboratory, Bar Harbor, ME.
Blood. 2019 Jan 24;133(4):331-343. doi: 10.1182/blood-2018-09-877787. Epub 2018 Nov 14.
Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The () transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially a result of the transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a transgenic mouse strain in which expression is driven by the endogenous locus. By crossing and mice to the dual-fluorescence reporter mouse and performing a head-to-head comparison, we demonstrate more stringent megakaryocyte lineage-specific expression of the transgene. Broader tissue expression was observed with the transgene, leading to recombination in many hematopoietic lineages, including monocytes, macrophages, granulocytes, and dendritic and B and T cells. Direct comparison of phenotypes of , or conditional KO mice generated using either the or strains revealed similar platelet phenotypes. However, additional inflammatory and immunological anomalies were observed in -generated KO mice as a result of nonspecific deletion in other hematopoietic lineages. By excluding leukocyte contributions to phenotypes, the mouse will advance our understanding of the role of platelets in inflammation and other pathophysiological processes in which platelet-leukocyte interactions are involved.
条件性敲除 (KO) 小鼠模型对于阐明血小板的生理作用非常重要。目前， () 转基因小鼠是生成巨核细胞/血小板特异性 KO 小鼠的首选模型。血小板和白细胞在广泛的疾病环境中密切合作，但血小板对这些过程的具体贡献仍不清楚。这部分是由于 转基因在多种白细胞群体中表达。为了解决这个问题，我们开发了一种 转基因小鼠品系，其中 表达受内源性 基因座驱动。通过将 和 小鼠与 双荧光报告小鼠杂交，并进行直接比较，我们证明了 转基因在更严格的巨核细胞谱系中特异性表达。观察到 转基因的组织表达更广泛，导致许多造血谱系中的重组，包括单核细胞、巨噬细胞、粒细胞、树突状细胞和 B 细胞和 T 细胞。使用 或 品系生成的 或 条件性 KO 小鼠的表型的直接比较显示出相似的血小板表型。然而，由于其他造血谱系中的非特异性缺失，在 -生成的 KO 小鼠中观察到额外的炎症和免疫异常。通过排除白细胞对表型的贡献， 小鼠将促进我们对血小板在涉及血小板-白细胞相互作用的炎症和其他病理生理过程中的作用的理解。
