We identified the BarH class homeodomain transcription factor gene
ceh-30 as a cell-specific regulator of the sexually dimorphic survival of the male-specific CEM sensory neurons.
ceh-30 activity in the CEMs is directly controlled by the sex-determination protein TRA-1. The cell-protective role of
ceh-30 is likely evolutionarily conserved: expression of the mouse
ceh-30 homolog Barhl1 can rescue the CEM survival defect of
ceh-30(lf) males, and Barhl1 knockout mice show a defect in the survival of differentiated sensory neurons highly reminiscent of the defect in CEM neuron survival of
ceh-30(lf) males. In the evolutionarily conserved core pathway for the execution of programmed cell death in C. elegans, the BH3-only Bcl-2 family killer protein EGL-1 negatively regulates the cell-protective Bcl-2-like protein CED-9. CED-9 acts through the adaptor CED-4 Apaf-1 to negatively regulate the caspase CED-3, which performs the cell-killing function. Nearly all regulators of programmed cell death known to function in C. elegans or in vertebrates act through the Bcl-2 superfamily. In particular, most regulators of specific cell deaths in C. elegans act through transcriptional control of the CED-9 regulator
egl-1, and these regulators are ineffective in animals lacking
ced-9 function. The deaths of the CEM neurons in hermaphrodites normally require the upstream killer gene
egl-1. However, when we activated the cell-death program by loss of function of the EGL-1 target CED-9, the deaths of the CEM neurons were regulated by sexual dimorphism and by
ceh-30 almost as well as they were in wild-type animals, even in animals also lacking
egl-1 function. Thus, although
egl-1 function is normally needed for the hermaphrodite CEMs to die, sex determination, acting through
ceh-30, regulates these deaths downstream of or in parallel to
egl-1 and
ced-9.
ceh-30 might therefore determine whether the CEMs are sensitive to the activation of programmed cell death, whether caused by expression of
egl-1 or by loss of
ced-9. This regulation by
ceh-30 does not require
bir-1 or
bir-2, the only known C. elegans homologs of vertebrate proteins that regulate apoptosis independently of the Bcl-2 superfamily.
ceh-30 appears to regulate cell survival by a mechanism distinct from any known to exist in vertebrate apoptosis. As the cell-protective function of
ceh-30 appears to be evolutionarily conserved, we propose that the mouse
ceh-30 homolog Barhl1 regulates apoptosis by a similarly novel mechanism.