ABSTRACT
The endoderm and much of the mesoderm arise from the EMS cell in the four-cell C. elegans embryo. We report that the MED-1 and -2 GATA factors specify the entire fate of EMS, which otherwise produces two C-like mesectodermal progenitors. The meds are direct targets of the maternal SKN-1 transcription factor; however, their forced expression can direct SKN-1-independent reprogramming of non-EMS cells into mesendodermal progenitors. We find that SGG-1/GSK-3beta kinase acts both as a Wnt-dependent activator of endoderm in EMS and an apparently Wnt-independent repressor of the meds in the C lineage, indicating a dual role for this kinase in mesendoderm development. Our results suggest that a broad tissue territory, mesendoderm, in vertebrates has been confined to a single cell in nematodes through a common gene regulatory network.
Subject(s)
Blastomeres/metabolism , Caenorhabditis elegans Proteins , Caenorhabditis elegans/metabolism , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , DNA-Binding Proteins/metabolism , Endoderm/metabolism , Helminth Proteins/metabolism , Mesoderm/metabolism , Transcription Factors/metabolism , Zebrafish Proteins , Amino Acid Sequence , Animals , Base Sequence , Blastomeres/cytology , Caenorhabditis elegans/cytology , Caenorhabditis elegans/embryology , Caenorhabditis elegans/genetics , Carrier Proteins/metabolism , Cell Differentiation , Cell Lineage , Cloning, Molecular , DNA/genetics , DNA/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Endoderm/cytology , Erythroid-Specific DNA-Binding Factors , GATA Transcription Factors , Glycogen Synthase Kinase 3 , Helminth Proteins/chemistry , Helminth Proteins/genetics , Mesoderm/cytology , Molecular Sequence Data , Mutation/genetics , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins/physiology , RNA-Binding Proteins , Signal Transduction , Stem Cells/cytology , Stem Cells/metabolism , Transcription Factors/chemistry , Transcription Factors/genetics , Wnt ProteinsABSTRACT
The signalling protein Wnt regulates transcription factors containing high-mobility-group (HMG) domains to direct decisions on cell fate during animal development. In Caenorhabditis elegans, the HMG-domain-containing repressor POP-1 distinguishes the fates of anterior daughter cells from their posterior sisters throughout development, and Wnt signalling downregulates POP-1 activity in one posterior daughter cell called E. Here we show that the genes mom-4 and lit-1 are also required to downregulate POP-1, not only in E but also in other posterior daughter cells. Consistent with action in a common pathway, mom-4 and lit-1 exhibit similar mutant phenotypes and encode components of the mitogen-activated protein kinase (MAPK) pathway that are homologous to vertebrate transforming-growth-factor-beta-activated kinase (TAK1) and NEMO-like kinase (NLK), respectively. Furthermore, MOM-4 and TAK1 bind related proteins that promote their kinase activities. We conclude that a MAPK-related pathway cooperates with Wnt signal transduction to downregulate POP-1 activity. These functions are likely to be conserved in vertebrates, as TAK1 and NLK can downregulate HMG-domain-containing proteins related to POP-1.
Subject(s)
Adaptor Proteins, Signal Transducing , Caenorhabditis elegans Proteins , Caenorhabditis elegans/genetics , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , DNA-Binding Proteins/genetics , Down-Regulation , High Mobility Group Proteins/genetics , Intracellular Signaling Peptides and Proteins , JNK Mitogen-Activated Protein Kinases , MAP Kinase Kinase Kinases , Mitogen-Activated Protein Kinase Kinases , Mitogen-Activated Protein Kinases , Proto-Oncogene Proteins/metabolism , Zebrafish Proteins , Amino Acid Sequence , Animals , Caenorhabditis elegans/enzymology , Caenorhabditis elegans/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line , Cloning, Molecular , Enzyme Activation , Gene Expression Regulation, Developmental , Genes, Helminth , Humans , MAP Kinase Kinase 4 , Membrane Proteins/genetics , Membrane Proteins/metabolism , Molecular Sequence Data , Potassium Channels, Voltage-Gated , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Sequence Homology, Amino Acid , Signal Transduction , Wnt ProteinsABSTRACT
The nuclear matrix is the nonchromatin scaffolding of the nucleus. This structure confers nuclear shape, organizes chromatin, and appears to contain important regulatory proteins. Tissue specific nuclear matrix proteins have been found in the rat, mouse, and human. In this study we compared high-resolution two-dimensional gel electropherograms of nuclear matrix protein patterns found in human colon tumors with those from normal colon epithelia. Tumors were obtained from 18 patients undergoing partial colectomy for adenocarcinoma of the colon and compared with tissue from 10 normal colons. We have identified at least six proteins which were present in 18 of 18 colon tumors and 0 of 10 normal tissues, as well as four proteins present in 0 of 18 tumors and in 10 of 10 normal tissues. These data, which corroborate similar findings of cancer-specific nuclear matrix proteins in prostate and breast, suggest that nuclear matrix proteins may serve as important markers for at least some types of cancer.
