An important feature of mammals is the sexually dimorphic reproductive tracts, which include external and internal sex organs. Abnormal development of the genital tubercle (GT), the common embryonic precursor of both male and female external genitalia, frequently results in birth defects including ambiguous genitalia and hypospadias but the underlying molecular basis is poorly understood. This proposal focuses on formation of the external genitalia, a significantly understudied area of embryology. Based on our preliminary data, we hypothesize that, in addition to the gonad-derived sex hormones such as androgens, Wnts expressed from the GT epithelium function as the permissive signal and; following the Wnt and androgen stimulation the gender-specific genomic activity of GT mesenchyme leads to formation of gender-specific external genital structures. We have designed three specific aims to test this hypothesis: 1) to examine whether Wnt4 is the permissive signal for dimorphic GT differentiation; 2) to determine whether sex hormones reprogram the GT- specific landscape of transcription enhancers to control dimorphic gene expression; and 3) to identify critical GT-specific downstream effectors of sex hormones that induce dimorphic GT differentiation to form penis in males and clitoris in females. We have developed and validated a suite of innovative genetic and genomic tools in order to achieve these specific aims. Findings from the proposed studies are expected to improve our understanding of sexual dimorphism in mammals, and to shed new light on the pathogenesis of common birth defects including ambiguous genitalia and hypospadias.

Public Health Relevance

This proposal aims to understand how the sex hormones induce dimorphic differentiation of genital tubercle to form either penis in males or clitoris in females. Genital anomalies including ambiguous genitalia, hypospadias and sex reversal are among the most common forms of birth defects but are poorly understood. Results from the proposed studies are expected to gain insight into the molecular basis of these birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK110477-01A1
Application #
9310760
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Hoshizaki, Deborah K
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Balsara, Zarine R; Li, Xue (2017) Sleeping beauty: awakening urothelium from its slumber. Am J Physiol Renal Physiol 312:F732-F743