Hypospadias or incomplete formation of the urethra is the most common congenital abnormality effecting penile development. Hypospadias has received very little basic research attention. The etiology remains undefined in the overwhelming majority of cases. Recent worldwide reports document an increase in the incidence of hypospadias. The main goal of this proposal is to investigate the mechanism of normal and abnormal urethral development in the mouse and in a mouse model of hypospadias secondary to endocrine disruptors. During normal development tubularization of the urethra requires urethral fold formation from the urethral plate, fusion of the urethral folds, formation of an epithelial seam and subsequent seam removal. In this grant we plan two related hypotheses. (#1) We hypothesize a novel mechanism that the urethral plate acts as the organizer of normal urethral development, directing urethral seam formation and remodeling via epithelial-mesenchymal interactions, and (#2) We hypothesize that maternal exposure to xogenous estrogens and/or antiandrogens disrupts these processes resulting in urethral disruption or hypospadias. To test these hypotheses, we plan four specific aims: (1) Define sexual dimorphism of the genital tubercle (GT) in the normal male and female mouse; (2) Define abnormal GT development in genetically engineered mice that spontaneous develop hypospadias or have GT abnormalities (Shh, Fgf-8, Fgf-10, Hoxa-13 and Igf- RI); (3) Induce abnormal genital development with maternal exposure to endocrine disruptors (synthetic estrogens and antiandrogens); and (4) Define the role of epithelial-mesenchymal interactions in penile growth, differentiation and urethra formation. The relevance of this proposal is that: (1) The mouse urethra develops in a similar fashion to the human urethra; (2) Defining the cellular and molecular mechanisms of hypospadias in the mouse is germane to understanding the human condition of hypospadias; and (3) If the endocrine disrupter theory can be definitely proven in the mouse, further efforts to document an endocrine disruptor hypothesis in humans is warranted. Ultimately preventative steps to decrease prenatal toxic exposure may be the must useful intervention with the mouse model providing a means to test suspected agents.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Rankin, Tracy L
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Isaacson, Dylan; Shen, Joel; Overland, Maya et al. (2018) Three-dimensional imaging of the developing human fetal urogenital-genital tract: Indifferent stage to male and female differentiation. Differentiation 103:14-23
Baskin, Laurence; Shen, Joel; Sinclair, Adriane et al. (2018) Development of the human penis and clitoris. Differentiation 103:74-85
Liu, Xin; Liu, Ge; Shen, Joel et al. (2018) Human glans and preputial development. Differentiation 103:86-99
Cunha, Gerald R; Robboy, Stanley J; Kurita, Takeshi et al. (2018) Development of the human female reproductive tract. Differentiation 103:46-65
Cunha, Gerald R; Kurita, Takeshi; Cao, Mei et al. (2018) Tissue interactions and estrogenic response during human female fetal reproductive tract development. Differentiation 101:39-45
Baskin, Laurence (2017) What Is Hypospadias? Clin Pediatr (Phila) 56:409-418
Robboy, Stanley J; Kurita, Takeshi; Baskin, Laurence et al. (2017) New insights into human female reproductive tract development. Differentiation 97:9-22
Isaacson, Dylan; Shen, Joel; Cao, Mei et al. (2017) Renal Subcapsular xenografing of human fetal external genital tissue - A new model for investigating urethral development. Differentiation 98:1-13
Isaacson, Dylan; Shen, Joel; McCreedy, Dylan et al. (2017) Dichotomous Branching of Human Fetal Lung Demonstrated with Light Sheet Fluorescence Microscopy. Am J Respir Crit Care Med 196:1476-1477
Baskin, Laurence S (2017) Restoring normal anatomy in female patients with atypical genitalia. Semin Perinatol 41:227-231

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