Functional analysis of mouse 3-phosphoglycerate dehydrogenase (Phgdh) gene by using gene targeting

d -3-磷酸甘油酸脱氢酶（Phgdh; EC 1.1.1.95）是l -丝氨酸生物合成磷酸化途径中第一个参与的酶。为了确定phgdh依赖的l -丝氨酸生物合成在体内的生理重要性，我们在胚胎斯坦细胞中使用靶向基因破坏产生phgdh缺陷小鼠。Phgdh的缺失导致l-丝氨酸代谢物如磷脂酰- l-丝氨酸（PS）和鞘脂的急剧减少。Phgdh无胚体小，在选定的组织中有异常，在性交后数天死亡。中枢神经系统明显异常，Phgdh null突变最终导致端脑、间脑和中脑发育不全；特别是嗅球、神经节隆起和小脑的结构模糊。这些观察结果表明，依赖phgdh的磷酸化途径对正常胚胎发育，特别是脑形态发生至关重要。

D-3-Phosphoglycerate dehydrogenase (Phgdh ; EC 1.1.1.95) is the first committed enzyme of L-serine biosynthesis in the phosphorylated pathway. To determine the physiological importance of Phgdh-dependent L-serine biosynthesis in vivo, we generated Phgdh-deficient mice using targeted gene disruption in embryonic stein cells. The absence of Phgdh led to a drastic reduction of L-serine metabolites such as phosphatidyl-L-serine (PS) and sphingolipids. Phgdh null embryos have small bodies with abnormalities in selected tissues and died after days post-coitum 13.5. Striking abnormalities were evident in the central nervous system in which the Phgdh null mutation culminated in hypoplasia of the telencephalon, diencephalon, and mesencephalon ; in particular, the olfactory bulbs, ganglionic eminence, and, cerebellum appeared as indistinct structures. These observations demonstrate that the Phgdh-dependent phosphorylated pathway is essential for normal embryonic development, especially for brain morphogenesis.