title: A Boolean network model of human gonadal sex determination.
abstract: BACKGROUND
  Gonadal sex determination (GSD) in humans is a complex biological process that takes place in early stages of embryonic development when the bipotential gonadal primordium (BGP) differentiates towards testes or ovaries. This decision is directed by one of two distinct pathways embedded in a GSD network activated in a population of coelomic epithelial cells, the Sertoli progenitor cells (SPC) and the granulosa progenitor cells (GPC). In males, the pathway is activated when the Sex-Determining Region Y (SRY) gene starts to be expressed, whereas in females the WNT4/ β-catenin pathway promotes the differentiation of the GPCs towards ovaries. The interactions and dynamics of the elements that constitute the GSD network are poorly understood, thus our group is interested in inferring the general architecture of this network as well as modeling the dynamic behavior of a set of genes associated to this process under wild-type and mutant conditions.
  
  
  METHODS
  We reconstructed the regulatory network of GSD with a set of genes directly associated with the process of differentiation from SPC and GPC towards Sertoli and granulosa cells, respectively. These genes are experimentally well-characterized and the effects of their deficiency have been clinically reported. We modeled this GSD network as a synchronous Boolean network model (BNM) and characterized its attractors under wild-type and mutant conditions.
  
  
  RESULTS
  Three attractors with a clear biological meaning were found; one of them corresponding to the currently known gene expression pattern of Sertoli cells, the second correlating to the granulosa cells and, the third resembling a disgenetic gonad.
  
  
  CONCLUSIONS
  The BNM of GSD that we present summarizes the experimental data on the pathways for Sertoli and granulosa establishment and sheds light on the overall behavior of a population of cells that differentiate within the developing gonad. With this model we propose a set of regulatory interactions needed to activate either the SRY or the WNT4/ β-catenin pathway as well as their downstream targets, which are critical for further sex differentiation. In addition, we observed a pattern of altered regulatory interactions and their dynamics that lead to some disorders of sex development (DSD).
authors.affiliation: Instituto Nacional de Pediatría, Laboratorio de Citogenética, Av. Insurgentes Sur 3700 C, México City, 04530, México. rios.osiris@gmail.com.|Programa de Doctorado en Ciencias Biológicas, UNAM, Mexico City, México. rios.osiris@gmail.com.
authors.forename: Osiris
authors.initials: O
authors.lastname: Ríos
authors.affiliation: Instituto Nacional de Pediatría, Laboratorio de Citogenética, Av. Insurgentes Sur 3700 C, México City, 04530, México. sarafrias@biomedicas.unam.mx.|Instituto de Investigaciones Biomédicas, UNAM, Mexico City, 04510, México. sarafrias@biomedicas.unam.mx.
authors.forename: Sara
authors.initials: S
authors.lastname: Frias
authors.affiliation: Instituto Nacional de Pediatría, Laboratorio de Citogenética, Av. Insurgentes Sur 3700 C, México City, 04530, México. alfrodriguezg@yahoo.com.|Programa de Doctorado en Ciencias Biomédicas, UNAM, Mexico City, México. alfrodriguezg@yahoo.com.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: Facultad de Medicina/Hospital General de Mexico, Mexico City, México.
authors.forename: Susana
authors.initials: S
authors.lastname: Kofman
authors.affiliation: Instituto de Investigaciones Biomédicas, UNAM, Mexico City, 04510, México. merchant@unam.mx.
authors.forename: Horacio
authors.initials: H
authors.lastname: Merchant
authors.affiliation: Instituto Nacional de Pediatría, Laboratorio de Citogenética, Av. Insurgentes Sur 3700 C, México City, 04530, México. ledactorres@gmail.com.
authors.forename: Leda
authors.initials: L
authors.lastname: Torres
authors.affiliation: Instituto de Investigaciones Biomédicas, UNAM, Mexico City, 04510, México. lmendoza@biomedicas.unam.mx.|C3, Centro de Ciencias de la Complejidad, UNAM, Mexico City, 04510, México. lmendoza@biomedicas.unam.mx.
authors.forename: Luis
authors.initials: L
authors.lastname: Mendoza
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D058490:Disorder of Sex Development, 46,XY / Q000473:pathology; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006066:Gonads; D006107:Granulosa Cells / Q000166:cytology; D006801:Humans; D008297:Male; D008954:Models, Biological; D012708:Sertoli Cells / Q000166:cytology; D019849:Sex Determination Processes
chemical_list: D050991:GATA4 Transcription Factor