Disorders of sexual differentiation (DSDs) are congenital conditions in which the phenotypic sex of an individual is atypical, often resulting from defects in hormonal signaling. Sexual differentiation of the urogenital sinus, the embryonic precursor to the urethra, is required for development of the prostate and other associated glands in males and for development of the vagina in females. Little is known about how the embryonic male and female urethra respond to hormonal cues to undergo sexual differentiation. This proposal aims to examine sexual differentiation of a structure called the sinus ridge, a thickened portion of the urogenital sinus where the ejaculatory ducts attach in the male and the developing vagina attaches in the female. The urogenital sinus and sinus ridge are initially identical in both sexes until hormone production begins in the embryonic gonads. Under hormonal influence, the sinus ridge is maintained internally in the male, while in the female, the ridge elongates and shifts caudally along the urogenital sinus until it reaches the base of the external genitalia, separating from the urethra to allow formation of a vaginal opening. It is not clear how development and subsequent sexual differentiation of the sinus ridge occurs, but the development of this structure is often perturbed in DSDs. For example, in males with reduced androgen signaling, the sinus ridge inappropriately shifts caudally and can lead to formation of a vaginal opening in these males. In females exposed to excess androgen embryonically, the vagina remains attached to the urethra internally and must be corrected surgically. This proposal will aid in the understanding of the urogenital phenotypes that result from DSDs by identifying how the sinus ridge develops in male mouse embryos lacking androgen signaling and in female mouse embryos exposed to excess androgen (Aim 1). In addition, the tissue population that requires androgen signaling for sinus ridge sexual differentiation will be determined through conditional deletion of the androgen receptor (Aim 2). Finally, targets of androgen that are responsible for sexual differentiation of the sinus ridge will be determined through a novel proteomics analysis of the mouse sinus ridge tissue (Aim 3). Besides this project having importance in our understanding of DSDs, the proposed research will be instrumental in the training and career development of the candidate, Dr. Christine Larkins. The proposed training plan will allow her to branch into new areas of research including developmental endocrinology and quantitative proteomics, it will give her the resources to attend courses and conferences relevant to her research and training, and will allow her to transition from a postdoctoral fellow to an independent researcher running her own lab.
The results of the aims described in this proposal will have an impact on our understanding of how urogenital phenotypes result from disorders of sexual differentiation. This proposal is specifically focused on how attenuated or abrogated androgen signaling affects differentiation of the urogenital sinus ridge, a structure whose development is disrupted in conditions such as Congenital Adrenal Hyperplasia or Androgen Insensitivity Syndrome. By understanding how androgen signaling leads to defects in urogenital structure, it will be possible to discover how these defects can be prevented.
| Larkins, Christine E; Enriquez, Ana B; Cohn, Martin J (2016) Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina. Proc Natl Acad Sci U S A 113:E7510-E7517 |
