Logical modelling uncovers developmental constraints for primary sex determination of chicken gonads

Abstract

In the chicken, sex determination relies on a ZZ (male)/ZW (female) chromosomal system, but underlying mechanisms are still not fully understood. The Z-dosage and the dominant W-chromosome hypotheses have been proposed to underlie primary sex determination. We present a modelling approach, which assembles the current knowledge and permits exploration of the regulation of this process in chickens. Relying on published experimental data, we assembled a gene network, which led to a logical model that integrates both the Z-dosage and dominant W hypotheses. This model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2, where the initial amount of DMRT1 product determines the development of the gonads. In this respect, at the initiation step, a W-factor would function as a secondary device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled, that is when the SOX9 functional level is established. Developmental constraints that are instrumental in this resolution were identified. These constraints establish qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. Our model further clarified the role of OESTROGEN in maintaining FOXL2 function during ovary development.

Keywords: chicken; gene regulatory network; logical modelling; primary sex determination.

Figure 1.

The (simplified) gene regulatory network controlling chicken primary sex determination (see electronic supplementary material, figure S1 for the complete network). Normal green and blunt red arrows represent positive and negative interactions, respectively, and dashed arrows indicate indirect or proposed interactions. Z1 and Z2 represent each a Z chromosome, whereas W represents a W chromosome; the sex chromosome constitution (ZW or ZZ) is thus specified by an adequate combination of these input components.

Figure 2.

Dynamics of the gene regulatory network for the ZZ and ZW chicken bi-potential gonads. Coloured (respectively, grey) arrows indicate operative (respectively, non-operative) interactions; components in red are at their maximal levels (pink for the intermediate level of DMRT1), white components are at their minimal level 0.

Figure 3.

Illustration of the concurrent events leading to distinct sexual fates for different chromosomal constitutions of the gonad. Priority settings to settle these conflicting events are proposed for the ZZ and ZW gonads (table 1). (Online version in colour.)