Mammalian external genital development requires a tightly coordinated network of signaling molecules and transcription factors. The Fibroblast Growth Factor (FGF) family of receptor tyrosine kinase (RTK) signaling molecules plays a central role in formation of the genital tubercle, which is the anlage of the glans penis and clitoris. Therefore, determining how the FGF pathway is regulated in the genital tubercle and which other pathways it interacts with will be critical to understanding the cellular mechanisms underlying malformations of the external genitalia. Sprouty (Spry) genes are important inhibitors of RTK signaling molecules, including FGFs. Loss of function mutations in Sprouty genes lead to hypersensitivity to FGF signaling, often resulting in abnormal cellular function and causing defects in several organs, including lungs, kidneys, teeth, and limbs. The regulation of FGF signaling by Sprouty genes led us to hypothesize that Sprouty genes play an important role in patterning of the external genitalia. We have recently found that combined deletion of Spry1 and Spry2 in mice results in hypospadias, a congenital anomaly in which the urethral meatus is abnormally placed along the ventral side of the glans penis rather than at the distal tip. Hypospadias is one of the most common birth defects, affecting approximately 1 in every 250-300 live male births. This condition, whose molecular etiology is poorly understood, can result in severe psycho-sexual problems and voiding abnormalities in spite of the best efforts at surgical reconstruction. Thus, there is a need for improved understanding of the etiology of the condition that could lead to better prenatal diagnosis as well as prevention and improved treatments. In this application, we will investigate how Sprouty genes control organogenesis of the mammalian external genitalia. By performing these studies, we will obtain fundamental insights into normal and abnormal genital tubercle morphogenesis.

Public Health Relevance

Hypospadias is one of the most common birth defects, affecting approximately 1 in every 250-300 live male births. This condition, whose molecular etiology is poorly understood, can result in severe psycho-sexual problems and voiding abnormalities in spite of the best efforts at surgical reconstruction. Thus, knowledge about the molecular pathways controlling genital development is of major clinical importance, and the experiments in this R01 application will enhance our knowledge of these pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK095002-01A1
Application #
8445140
Study Section
Special Emphasis Panel (ZRG1-KMBD-C (02))
Program Officer
Hoshizaki, Deborah K
Project Start
2012-09-18
Project End
2014-08-31
Budget Start
2012-09-18
Budget End
2014-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$150,000
Indirect Cost
$54,204
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ching, Saunders T; Cunha, Gerald R; Baskin, Laurence S et al. (2014) Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia. Dev Biol 386:1-11
Juuri, Emma; Jussila, Maria; Seidel, Kerstin et al. (2013) Sox2 marks epithelial competence to generate teeth in mammals and reptiles. Development 140:1424-32
Oishi, Peter E; Klein, Ophir D; Keller, Roberta L et al. (2013) Developing physician-scientists in the fields of neonatology and pediatric critical care medicine: an effort to formulate a departmental policy. J Pediatr 163:616-7.e1