Xue Y, Wang X, Li Z, Gotoh N, Chapman D, Skolnik E Y
New York University Medical Center, Skirball Institute of Biomolecular Medicine, Department of Pharmacology, NY, NY10016, USA.
Development. 2001 May;128(9):1559-72. doi: 10.1242/dev.128.9.1559.
We have previously shown that the Drosophila Ste20 kinase encoded by misshapen (msn) is an essential gene in Drosophila development. msn function is required to activate the Drosophila c-Jun N-terminal kinase (JNK), basket (Bsk), to promote dorsal closure of the Drosophila embryo. Later in development, msn expression is required in photoreceptors in order for their axons to project normally. A mammalian homolog of msn, the NCK-interacting kinase (NIK) (recently renamed to mitogen-activated protein kinase kinase kinase kinase 4; Map4k4), has been shown to activate JNK and to bind the SH3 domains of the SH2/SH3 adapter NCK. To determine whether NIK also plays an essential role in mammalian development, we created mice deficient in NIK by homologous recombination at the Nik gene. Nik(-/-) mice die postgastrulation between embryonic day (E) 9.5 and E10.5. The most striking phenotype in Nik(-/-) embryos is the failure of mesodermal and endodermal cells that arise from the anterior end of the primitive streak (PS) to migrate to their correct location. As a result Nik(-/- )embryos fail to develop somites or a hindgut and are truncated posteriorly. Interestingly, chimeric analysis demonstrated that NIK has a cell nonautonomous function in stimulating migration of presomitic mesodermal cells away from the PS and a second cell autonomous function in stimulating the differentiation of presomitic mesoderm into dermomyotome. These findings indicate that despite the large number of Ste20 kinases in mammalian cells, members of this family play essential nonredundant function in regulating specific signaling pathways. In addition, these studies provide evidence that the signaling pathways regulated by these kinases are diverse and not limited to the activation of JNK because mesodermal and somite development are not perturbed in JNK1-, and JNK2-deficient mice.
我们之前已经表明，由畸形基因（msn）编码的果蝇Ste20激酶是果蝇发育中的一个必需基因。激活果蝇c-Jun氨基末端激酶（JNK）、篮状蛋白（Bsk）以促进果蝇胚胎背侧闭合需要msn发挥功能。在发育后期，感光细胞中需要msn表达，以便其轴突正常投射。msn的一个哺乳动物同源物，即NCK相互作用激酶（NIK）（最近更名为丝裂原活化蛋白激酶激酶激酶激酶4；Map4k4），已被证明可激活JNK并结合SH2/SH3衔接蛋白NCK的SH3结构域。为了确定NIK在哺乳动物发育中是否也发挥重要作用，我们通过在Nik基因处进行同源重组创建了NIK缺陷型小鼠。Nik(-/-)小鼠在原肠胚形成后于胚胎第9.5天至第10.5天死亡。Nik(-/-)胚胎中最显著的表型是源自原始条纹（PS）前端的中胚层和内胚层细胞无法迁移到其正确位置。因此，Nik(-/-)胚胎无法发育出体节或后肠，并且在后端被截断。有趣的是，嵌合体分析表明，NIK在刺激前体节中胚层细胞从PS迁移方面具有细胞非自主功能，在刺激前体节中胚层分化为皮肌节方面具有第二种细胞自主功能。这些发现表明，尽管哺乳动物细胞中有大量的Ste20激酶，但该家族成员在调节特定信号通路中发挥着重要的非冗余功能。此外，这些研究提供了证据，证明这些激酶调节的信号通路是多样的，并不局限于JNK的激活，因为在JNK1和JNK2缺陷型小鼠中，中胚层和体节发育并未受到干扰。
