The genetics of the sexually dimorphic deaths of the C. elegans CEM neutrons

Abstract

The cells of metazoan organisms possess the capability to commit a form of cellular suicide known as programmed cell death or apoptosis. The proper control of this endogenous death program is essential to animal development and to the prevention of disease. To better understand how individual cells are developmentally specified to die, I studied the survival decision of a single cell type in the nematode Caenorhabditis elegans, the CEM neurons. The CEMs die during hermaphrodite embryogenesis and survive and function as sensory neurons in males. I identified 144 independent mutant strains in which the CEM neurons of hermaphrodites survive, including 52 mutants in known cell-death genes and 67 mutants generally defective sex determination. Another 29 screen isolates displayed a new defect of transcriptional de repression, the green pharynx phenotype. From these isolates and from additional screens, I defined a set of seven genes that function to prevent inappropriate gene expression. From the isolates causing CEM survival I identified two new sex-determination proteins, the PLZF-like transcription factor TRA-4 and the F-box protein SEL-10; demonstrated that the neurogenesis genes vab-3 Pax6 and cnd-1 NeuroD are required for aspects of the CEM fate, including CEM death, and likely function together in this process and in other aspects of C. elegans development, a cooperative relationship likely to be evolutionarily conserved; and identified the Bar family homeodomain transcription factor gene ceh-30 as specifically promoting CEM survival. The CEM neurons of males lacking ceh-30 inappropriately undergo programmed cell death. In the CEMs of hermaphrodites, ceh-30 is directly repressed by TRA-1, a transcription factor that acts as the last step in the sex-determination pathway to promote a hermaphrodite identity.

(cont.) The cell-protective function of ceh-30 is specific to the CEM neurons, and ceh-30 is expressed in and acts cell-autonomously in the CEMs to promote their survival. Expression of the mouse ceh-30 homolog Barhll can restore CEM survival to ceh-30 mutants. In mice lacking Barhl1, as in ceh-30 mutants, a specific class of sensory neuron is generated normally differentiates, but subsequently inappropriately undergoes apoptotic cell death. Protection of the CEM neurons by ceh-30 does not require CED-9, the sole member of the multidomain Bcl-2 family in C. elegans. By contrast, other regulators of the survival decisions of specific cells in C. elegans act through transcriptional control of the CED-9 inhibitor egl-1. Mammalian regulation of cell death is similarly almost entirely mediated through members of the multidomain Bcl-2 family. The evolutionarily conserved cell-protective function of ceh-30 therefore probably defines a previously unknown mechanism capable of promoting cell survival both in nematode development, in the sensory neurons required for hearing in the mouse and likely in humans.