The nuclear receptors constitute a class of conserved transcription factors that function in regulating animal development. The NR2E subclass nuclear receptor
fax-1 of C. elegans functions in the specification of neurons, including neurotransmitter receptor expression and axon pathfinding functions. The Drosophila ortholog of
fax-1, unfulfilled, functions in the differentiation of mushroom body neurons, including their normal arborization properties. In addition, unfulfilled has been shown to regulate period in pacemaker neurons in cooperation with another evolutionarily-conserved nuclear receptor E75, which is Rev-erb-a (NR1D1) in vertebrates. The C. elegans ortholog of E74 is
nhr-85, which prompted us to investigate similar cooperative functions between
fax-1 and
nhr-85. We have found that both
fax-1 and
nhr-85 are expressed in the migrating distal-tip cells (DTCs) of the hermaphrodite gonad from L2 through L4 stages. Loss of both
fax-1 and
nhr-85 results in a low-penetrance DTC migration defect.
fax-1;
nhr-85 double mutants display DTC migration defects that are similar, consistent with a model in which they act together in a linear pathway. Loss of
fax-1 results in a significant reduction in brood size. The reduction in offspring appears to result from a defect in sperm production rather than oogenesis. This might possibly result from compromised DTC migration or function. We are currently investigating whether
nhr-85 mutations cause a similar effect. The
vab-3 transcription factor plays a key role in regulating the migrations of the DTCs. In
vab-3 mutants, the DTCs continue to migrate into adulthood and also fail to turn off
fax-1, suggesting that expression of
fax-1 is a property of a migrating DTC. A mutation in
fax-1 does not suppress the
vab-3 migration defect, indicating that
fax-1 is not an essential downstream mediator of
vab-3 function. We propose that
fax-1 and
nhr-85 function in DTC migration is a robustness phenomenon. Unlike Drosophila,
fax-1 and
nhr-85 function appear to overlap in a very limited number of cells-perhaps just the DTCs. This possibility limits the importance of co-regulation by FAX-1 and NHR-85 in C. elegans, indicating that evolution within ecdysozoa has led to different function roles for these nuclear receptors. Supported by NIGMS.