Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK).
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.
Xue
Y
Y
New York University Medical Center, Skirball Institute of Biomolecular Medicine, Department of Pharmacology, NY, NY10016, USA.
Wang
X
X
Li
Z
Z
Gotoh
N
N
Chapman
D
D
Skolnik
E Y
EY
D000818:Animals; D019521:Body Patterning; D002678:Chimera; D029721:Drosophila Proteins; D020964:Embryo Loss; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D005775:Gastrula; D018390:Gene Targeting; D005804:Genes, Lethal; D006720:Homozygote; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D008648:Mesoderm; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009420:Nervous System / Q000196:embryology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011995:Recombination, Genetic; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D019170:Somites / Q000166:cytology; D013234:Stem Cells
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; C113875:msn protein, Drosophila; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C078754:STE20 protein, S cerevisiae