Genetic regulation of sex determination in C. elegans

Sex determination regulates cell fate throughout the animal.

C. elegans develops as either a self-fertilizing hermaphrodite or a male depending on its relative X chromosome dose, or X:autosome (X:A) ratio. Diploid individuals with 2 X chromosomes develop as hermaphrodites, and those with one X chromosome develop as males. The two sexes differ morphologically, anatomically, and behaviourally as a result of the sex-specific differentiation of hundreds of cells, including representatives of every tissue. Mutations that cause animals to develop with a sexual phenotype that is inappropriate for their X:A ratio identify most of the major sex-determining genes. Some genes are required both for sex determination and for X chromosome dosage compensation: mutations in these genes are lethal either to XX or XO animals. The activities of the sex-determining genes respond to the X:A ratio and regulate sexual differentiation throughout the animal.

The genetic model of sex determination.

Epistasis analysis of mutations in the sex-determining genes suggests a model for the genetic control of somatic sex determination, represented by the diagram below. (Sex determination in the germline involves additional regulators and interactions.)

The key features of the model are:

each sex-determining gene promotes either male- or female-specific cell fates; (in the diagram, genes required for male fates are shown in blue, and those required for female fates are in red)
the sex-determining genes act in a hierarchy, in which genes at one level negatively regulate genes at the next level;
the X:A ratio sets the pathway to one of two essentially reciprocal states;
the output of the pathway is whether the activity of its ultimate gene, tra-1, is high or low;
tra-1 activity is necessary and sufficient to promote female cell fates (and inhibit male cell fates) in all somatic tissues; male somatic development, on the contrary, results when tra-1 is inactive.

We are interested in the mechanisms that regulate tra-1 activity. Central to these mechanisms are three fem genes, so-called because the loss of any one of them completely feminizes both XO and XX animals, transforming them into fertile, true females. The fem genes promote male cell fates by negatively regulating tra-1 throughout the nematode. In the germline, they also act through additional targets to promote spermatogenesis.

A sex-determining signal transduction pathway

In the context of the genetic model, the sequences of the sex-determining genes suggest that their products are components of a signal transduction pathway. The main target of this pathway is the transcription factor, TRA-1A, encoded by tra-1.

The secreted signal that regulates TRA-1A is the product of the her-1 gene. HER-1 is synthesized only when the X:A ratio is low, as in XO diploid animals. It inactivates a large transmembrane protein, TRA-2A, encoded by tra-2. The action of HER-1 relieves the inhibitory effect of TRA-2A on the FEM proteins, allowing them to inhibit TRA-1A and bring about male development.

When the X:A ratio is high, as in XX diploid animals, the activities of the sdc genes repress her-1 transcription. With no HER-1 protein around, TRA-2A inhibits the FEM proteins, allowing TRA-1A to cause female development.