The kinase SGK1 in the endoderm and mesoderm promotes ectodermal survival by down-regulating components of the death-inducing signaling complex.
A balance between cell survival and apoptosis is essential for animal development. Although proper development involves multiple interactions between germ layers, little is known about the intercellular and intertissue signaling pathways that promote cell survival in neighboring or distant germ layers. We found that serum- and glucocorticoid-inducible kinase 1 (SGK1) promoted ectodermal cell survival during early Xenopus embryogenesis through a non-cell-autonomous mechanism. Dorsal depletion of SGK1 in Xenopus embryos resulted in shortened axes and reduced head structures with defective eyes, and ventral depletion led to defective tail morphologies. Although the gene encoding SGK1 was mainly expressed in the endoderm and dorsal mesoderm, knockdown of SGK1 caused excessive apoptosis in the ectoderm. SGK1-depleted ectodermal explants showed little or no apoptosis, suggesting non-cell-autonomous effects of SGK1 on ectodermal cells. Microarray analysis revealed that SGK1 knockdown increased the expression of genes encoding FADD (Fas-associated death domain protein) and caspase-10, components of the death-inducing signaling complex (DISC). Inhibition of DISC function suppressed excessive apoptosis in SGK1-knockdown embryos. SGK1 acted through the transcription factor nuclear factor κB (NF-κB) to stimulate production of bone morphogenetic protein 7 (BMP7), and overexpression of BMP7 in SGK1-knockdown embryos reduced the abundance of DISC components. We show that phosphoinositide 3-kinase (PI3K) functioned upstream of SGK1, thus revealing an endodermal and mesodermal pathway from PI3K to SGK1 to NF-κB that produces BMP7, which promotes ectodermal survival by decreasing DISC function.
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Tatsuya
T
Endo
Morioh
M
Kusakabe
Kazunori
K
Sunadome
Takuya
T
Yamamoto
Eisuke
E
Nishida
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004475:Ectoderm / Q000378:metabolism / Q000502:physiology*; D004707:Endoderm / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008156:Luciferases; D008648:Mesoderm / Q000378:metabolism; D046228:Microarray Analysis; D024101:Mitochondrial Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D055419:Bone Morphogenetic Protein 7; D017874:Immediate-Early Proteins; D008156:Luciferases; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009841:Oligonucleotides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D029867:Xenopus Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C503369:GRAMD4 protein, human; C525822:bmp7.1 protein, Xenopus