Cohn Group (GUDMAP2)
Congenital malformations of the external genitalia are among the most common birth defects in humans. Hypospadias is a structural defect of the penis that is characterized by incomplete formation of the urethral tube and associated stromal tissues. Affected children can have oversized, ectopic or multiple urethral openings and, in severe cases, ambiguous genitalia. All but the mildest forms require surgical intervention. The incidence of hypospadias more than doubled over the past 40 years and now affects ~1 of every 250 live births. Despite the magnitude of this public health problem, little is known about the molecular mechanisms of urethral or external genital development.
Very few genes have been implicated in external genital development, which limits both our understanding of the molecular underpinnings of congenital anomalies and the possibilities for genetic screening. Fetal exposure to endocrine disrupting chemicals also may play a role in hypospadias. Whether the causes of hypospadias are genetic, environmental, or a combination of both, development of preventative strategies (and cell-based therapies for repair or regeneration of urologic tissues) will require knowledge of the genetic programs that direct cell fate decisions and tissue morphogenesis during external genital development.
The roles of our laboratory in GUDMAP2 are (1) to develop a three-dimensional anatomical reference atlas of the developing male and female external genitalia over developmental time, (2) to uncover new molecular markers for the endodermal cell types will form the urethral epithelium, and (3) to map 3-D patterns of gene expression in the developing genital tubercle and associated urethra to this new anatomical reference series. These objectives will be accomplished by integrating gene expression analysis, three-dimensional imaging technology (Optical Projection Tomography) and NexGen RNA sequencing.
Grant number: 5U01DK094523
Links to files for paper: Molecular characterization of the genital organizer: Gene expression profile of the mouse urethral plate epithelium, Journal of Urology, Armfield et al. (2016)
- Table 1: Genes with >20 fold expression differences in the endoderm vs surrounding tissue of the genital tubercle at E12.5 (PDF)