Qu C K, Yu W M, Azzarelli B, Cooper S, Broxmeyer H E, Feng G S
Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5254, USA.
Mol Cell Biol. 1998 Oct;18(10):6075-82. doi: 10.1128/MCB.18.10.6075.
Shp-2 is a cytoplasmic tyrosine phosphatase that contains two Src homology 2 (SH2) domains at the N terminus. Biochemical data suggests that Shp-2 acts downstream of a variety of receptor and cytoplasmic tyrosine kinases. A targeted deletion mutation in the N-terminal SH2 (SH2-N) domain results in embryonic lethality of homozygous mutant mice at midgestation. In vitro embryonic stem (ES) cell differentiation assays suggest that Shp-2 might play an important role in hematopoiesis. By aggregating homozygous mutant (Shp-2(-/-)) ES cells and wild-type (WT) embryos, we created Shp-2(-/-)-WT chimeric animals. We report here an essential role of Shp-2 in the control of blood cell development. Despite the widespread contribution of mutant cells to various tissues, no Shp-2(-/-) progenitors for erythroid or myeloid cells were detected in the fetal liver and bone marrow of chimeric animals by using the in vitro CFU assay. Furthermore, hematopoiesis was defective in Shp-2(-/-) yolk sacs. In addition, the Shp-2 mutation caused multiple developmental defects in chimeric mice, characterized by short hind legs, aberrant limb features, split lumbar vertebrae, abnormal rib patterning, and pathological changes in the lungs, intestines, and skin. These results demonstrate a functional involvement of Shp-2 in the differentiation of multiple tissue-specific cells and in body organization. More importantly, the requirement for Shp-2 is more stringent in hematopoiesis than in other systems.
Shp-2是一种细胞质酪氨酸磷酸酶，在N端含有两个Src同源2（SH2）结构域。生化数据表明，Shp-2在多种受体和细胞质酪氨酸激酶的下游发挥作用。N端SH2（SH2-N）结构域的靶向缺失突变导致纯合突变小鼠在妊娠中期胚胎致死。体外胚胎干细胞（ES）分化试验表明，Shp-2可能在造血过程中发挥重要作用。通过将纯合突变（Shp-2(-/-)）ES细胞与野生型（WT）胚胎聚集，我们创建了Shp-2(-/-)-WT嵌合动物。我们在此报告Shp-2在控制血细胞发育中的重要作用。尽管突变细胞广泛参与各种组织，但通过体外CFU试验，在嵌合动物的胎肝和骨髓中未检测到红细胞或髓细胞的Shp-2(-/-)祖细胞。此外，Shp-2(-/-)卵黄囊中的造血功能存在缺陷。此外，Shp-2突变导致嵌合小鼠出现多种发育缺陷，其特征为后腿短小、肢体特征异常、腰椎椎骨分裂、肋骨排列异常以及肺、肠和皮肤的病理变化。这些结果表明Shp-2在多种组织特异性细胞的分化和身体组织中发挥功能作用。更重要的是，造血过程中对Shp-2的需求比其他系统更为严格。
