Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only gene egl-1 in Caenorhabditis elegans.
The decision of a cell to undergo programmed cell death is tightly regulated during animal development and tissue homeostasis. Here, we show that the Caenorhabditis elegans Six family homeodomain protein C. elegans homeobox (CEH-34) and the Eyes absent ortholog EYA-1 promote the programmed cell death of a specific pharyngeal neuron, the sister of the M4 motor neuron. Loss of either ceh-34 or eya-1 function causes survival of the M4 sister cell, which normally undergoes programmed cell death. CEH-34 physically interacts with the conserved EYA domain of EYA-1 in vitro. We identify an egl-1 5' cis-regulatory element that controls the programmed cell death of the M4 sister cell and show that CEH-34 binds directly to this site. Expression of the proapoptotic gene egl-1 in the M4 sister cell requires ceh-34 and eya-1 function. We conclude that an evolutionarily conserved complex that includes CEH-34 and EYA-1 directly activates egl-1 expression through a 5' cis-regulatory element to promote the programmed cell death of the M4 sister cell. We suggest that the regulation of apoptosis by Six and Eya family members is conserved in mammals and involved in human diseases caused by mutations in Six and Eya.
Hirose
Takashi
T
Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Galvin
Brendan D
BD
Horvitz
H Robert
HR
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001665:Binding Sites / Q000235:genetics; D017173:Caenorhabditis elegans / Q000166:cytology / Q000196:embryology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010614:Pharynx / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
C543914:CEH-34 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C112486:EGL-1 protein, C elegans; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D017027:Protein Tyrosine Phosphatases; C506511:eya-1 protein, C elegans