A mutation in teg-4, which encodes a protein homologous to the SAP130 pre-mRNA splicing factor, disrupts the balance between proliferation and differentiation in the C. elegans germ line.
Dividing stem cells can give rise to two types of daughter cells; self-renewing cells that have virtually the same properties as the parent cell, and differentiating cells that will eventually form part of a tissue. The Caenorhabditis elegans germ line serves as a model to study how the balance between these two types of daughter cells is maintained. A mutation in teg-4 causes over-proliferation of the stem cells, thereby disrupting the balance between proliferation and differentiation. We have cloned teg-4 and found it to encode a protein homologous to the highly conserved splicing factor subunit 3 of SF3b. Our allele of teg-4 partially reduces TEG-4 function. In an effort to determine how teg-4 functions in controlling stem cell proliferation, we have performed genetic epistasis analysis with known factors controlling stem cell proliferation. We found that teg-4 is synthetic tumorous with genes in both major redundant genetic pathways that function downstream of GLP-1/Notch signaling to control the balance between proliferation and differentiation. Therefore, teg-4 is unlikely to function specifically in either of these two genetic pathways. Further, the synthetic tumorous phenotype seen with one of the genes from these pathways is epistatic to glp-1, indicating that teg-4 functions downstream of glp-1, likely as a positive regulator of meiotic entry. We propose that a reduction in teg-4 activity reduces the splicing efficiency of targets involved in controlling the balance between proliferation and differentiation. This results in a shift in the balance towards proliferation, eventually forming a germline tumor.
Mantina
Pallavi
P
Department of Biological Sciences, University of Calgary, Alberta, Canada.
MacDonald
Lindsay
L
Kulaga
Adam
A
Zhao
Lina
L
Hansen
Dave
D
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000166:cytology / Q000196:embryology / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004843:Epistasis, Genetic; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism; D007814:Larva / Q000254:growth & development; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D021122:Protein Subunits / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000737:chemistry*; D051880:Receptors, Notch / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013696:Temperature
D029742:Caenorhabditis elegans Proteins; C060620:Glp-1 protein, C elegans; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D051880:Receptors, Notch