Sex determination

Primary sex determination of chicken gonads

Summary:

This logical model assembles the current knowledge on the regulation of primary sex determination in chicken. Relying on experimental data, a gene network was constructed, leading to a logical model that integrates both the Z-dosage and dominant W hypotheses. The model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2; the initial amount of DMRT1 product determines the development of the gonads. In this respect, the W-factor functions at the initiation step as a second device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled; i.e. when SOX9 functional state is determined. Developmental constraints that are instrumental in this resolution were identified. These constraints correspond to qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. The model further clarified the role of oestrogen in maintaining FOXL2 function during ovary development.

Curation

Submitter:

C. Chaouiya

Supporting Paper :

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

Model metadata

Model file(s):

full_network.zginml

Model file(s):

reduced_network.zginml

Model file(s):

full_network.sbml

Model file(s):

reduced_network.sbml

Description:

GINsim and SBML qual files for the full and reduced networks (Fig S1 and Fig1)

Primary sex determination of placental mammals

Summary:

Background
Primary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules.
Results
Relying on a comprehensive revision of the literature, we define a logical model that integrates the current knowledge of the regulatory network controlling this developmental process. Our analysis indicates the necessity for some genes to operate at distinct functional thresholds and for specific developmental conditions to ensure the reproducibility of the sexual pathways followed by bi-potential gonads developing into either testes or ovaries. Our model thus allows studying the dynamics of wild type and mutant XX and XY gonads. Furthermore, the model analysis reveals that the gonad sexual fate results from the operation of two sub-networks associated respectively with an initiation and a maintenance phases. At the core of the process is the resolution of two connected feedback loops: the mutual inhibition of Sox9 and ß-catenin at the initiation phase, which in turn affects the mutual inhibition between Dmrt1 and Foxl2, at the maintenance phase. Three developmental signals related to the temporal activity of those sub-networks are required: a signal that determines Sry activation, marking the beginning of the initiation phase, and two further signals that define the transition from the initiation to the maintenance phases, by inhibiting the Wnt4 signalling pathway on the one hand, and by activating Foxl2 on the other hand.
Conclusions
Our model reproduces a wide range of experimental data reported for the development of wild type and mutant gonads. It also provides a formal support to crucial aspects of the gonad sexual development and predicts gonadal phenotypes for mutations not tested yet.

Curation

Submitter:

C. Chaouiya

Supporting Paper :

Primary sex determination of placental mammals: a modelling study uncovers dynamical developmental constraints in the formation of Sertoli and granulosa cells.

Model metadata

Model file(s):

primary_sex_determination_1.zginml

Model file(s):

primary_sex_determination_2.zginml

Description:

primary_sex_determination_1.zginml is the model file for the single cell network

Description:

primary_sex_determination_2.zginml is the model file for the two-cell network