In mammals, sex determination is the embryonic process that determines the developmental fate of the bipotential gonad into either testis or ovary. It is triggered by the presence, in males, or the absence in females, of Sry, a Y-linked gene encoding a transcription factor. Disorders of human sex determination cause defects in gonadal function and can result in a spectrum of abnormalities in the internal and external genitalia, ranging from mild sexual ambiguities to complete sex reversal. Although several sex-determining genes have been identified in humans and mouse models, the vast majority of XY patients with disorders of sex determination are not explained genetically, suggesting the existence of other genetic factors involved in this process. In addition, the molecular mechanisms of known sex-determining genes are poorly understood. Our overarching goal is to decipher the molecular events underlying the differentiation of the embryonic gonad, and therefore the process of sex determination. To achieve this objective, we will investigate a mouse model of disorders of sex development. We will identify novel genetic factors protecting against XY sex reversal in the C57BL/6J-YPOS mouse model in which the combination of a Y chromosome originating from a domesticus strain (YPOS) and a C57BL/6J background results in disrupted testicular development. Since our preliminary results show that a congenic region from mouse chromosome 11 protects against sex reversal in the C57BL/6J-YPOS model, we will test the hypothesis that this congenic region carries one or several genes that differ between C57BL/6J and the donor, congenic, fragment and that the difference is responsible for the protection. We will narrow down the congenic region by creating sub-congenic areas and identifying a minimal congenic fragment associated with the protection phenotype (Aim 1). We will also screen for and select candidate genes, investigate their expression profile and their functional relationship with known sex-determining genes and test if the alteration of their expression causes modifications in embryonic gonadal development (Aim 2). Finally, we will investigate the molecular mechanisms of XY sex reversal in the C57BL/6J-YPOS model and analyze the molecular and cellular nature of protective effect from the congenic region on gonadal development (Aim 3). Dissecting the molecular pathway of mammalian sex determination will be crucial in understanding the basic sex differences in gonadal development and the pathophysiology of human disorders of sex development.

Public Health Relevance

One of the most defining moment of our lives is when, in the womb, we embark on a male or female path, and what triggers this moment is when the gene Sry is turned on in males, or stays off in females;yet, many molecular events that happen after Sry action remain poorly understood, and in humans, disruption of sexual development occurs at a frequency of 0.5% to 1%. As only 25% of human pathologies of sex determination are explained genetically, we propose to identify new genes involved in this process by using a mouse model of abnormal sex development. This proposal will elucidate basic questions about how males and females become different, and will improve genetic classification and diagnostic methods of patients born with disorders of sex development.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-A (02))
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Taymans, Susan
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Ngun, Tuck C; Ghahramani, Negar M; Creek, Michelle M et al. (2014) Feminized behavior and brain gene expression in a novel mouse model of Klinefelter Syndrome. Arch Sex Behav 43:1043-57
Arboleda, Valerie A; Fleming, Alice; Barseghyan, Hayk et al. (2014) Regulation of sex determination in mice by a non-coding genomic region. Genetics 197:885-97
Caburet, Sandrine; Arboleda, Valerie A; Llano, Elena et al. (2014) Mutant cohesin in premature ovarian failure. N Engl J Med 370:943-949
Arboleda, V A; Lee, H; Sánchez, F J et al. (2013) Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development. Clin Genet 83:35-43
Baxter, Ruth M; Vilain, Eric (2013) Translational genetics for diagnosis of human disorders of sex development. Annu Rev Genomics Hum Genet 14:371-92
Fleming, Alice; Ghahramani, Negar; Zhu, Maggie Xiaoming et al. (2012) Membrane ?-catenin and adherens junctions in early gonadal patterning. Dev Dyn 241:1782-98
Sutton, Edwina; Hughes, James; White, Stefan et al. (2011) Identification of SOX3 as an XX male sex reversal gene in mice and humans. J Clin Invest 121:328-41
Arboleda, Valerie A; Vilain, Eric (2011) The evolution of the search for novel genes in mammalian sex determination: from mice to men. Mol Genet Metab 104:67-71
White, Stefan; Ohnesorg, Thomas; Notini, Amanda et al. (2011) Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One 6:e17793
Vilain, Eric (2011) The genetics of ovotesticular disorders of sex development. Adv Exp Med Biol 707:105-6

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