Molecular Genetics of External Genital Development
Congenital malformations of the external genitalia are among the most common birth defects. Approximately one in every 250 children is now born with hypospadias, a malformation affecting urethral tube development. A major focus of our lab is to understand the molecular control of external genital patterning in mammals. This project focuses heavily on the mouse as a model system, and involves molecular genetics, experimental embryology, and genomic analysis of genitourinary development. The external genitalia of males and females begin with formation of a genital tubercle. Signals that regulate early pattern formation of the genital tubercle are common to males and females, and sexual differentiation occurs relatively late in genitourinary morphogenesis. We are interested in identifying genes that (1) regulate development of the urethral tube, and (2) control outgrowth and three-dimensional patterning of the genital tubercle. We have discovered a new organizer that is essential for early outgrowth of the genital tubercle. The activity of this organizing tissue is mediated by a secreted signaling molecule called Sonic hedgehog. We have also identified a growth factor receptor that plays an essential role in urethral tube closure. This work has opened a new area of investigation, providing the opportunity to study how environmental factors influence the genetic circuitry that regulates embryonic development. The lab also has a strong interest in the evolution of external genitalia. We are addressing questions aimed at identifying the mechanisms responsible for this major morphological innovation, and understanding how genitourinary structures have diversified during tetrapod evolution.
Representative Papers
Seifert, A. W., Yamaguchi, T. and Cohn, M. J. (2009). Functional and phylogentic analysis shows that Fgf8 is not required for external genital development. Development 136: 2643-51.
Seifert, A. W., Harfe, B. D. and Cohn, M. J. (2008) Cell lineage analysis demonstrates an endodermal origin of the distal urethra and perineum. Developmental Biology 318:143-152.
Petiot, A., Perriton, C. L., Dickson, C., and Cohn, M. J. (2005). Development of the mammalian urethra is controlled by FgfR2-IIIb. Development. 132:2441-2450.
Perriton, C. L., Powles, N., Chiang, C., Maconochie, M., and Cohn, M. J. (2002) Sonic hedgehog signaling from the urethral plate controls external genital development. Developmental Biology. 247:26-46.
Evolution of Vertebrate Limb Development
Our lab aims to understand the molecular genetic mechanisms responsible for the evolution of fins and limbs. How the vertebrate limb is constructed during embryonic development is becoming increasingly clear, but comparatively little is known about how this genetic program has evolved to generate the impressive morphological diversity seen across vertebrates. This project is focused on identifying the developmental genetic causes of major evolutionary changes to the vertebrate body, such as the origin of fins, the transition of fins to limbs, and loss of limbs in animals such as snakes and whales. These questions are being addressed by a comparative approach to developmental biology, in which the molecular control of embryonic development is studied in a range of organisms that sit at key phylogenetic positions.
Representative Papers
Zhang, G. and Cohn, M. J. (2008). Genome duplication and the origin of the vertebrate skeleton. Current Opinion in Genetics and Development 18:3-9.
Zhang, G. and Cohn, M. J. (2006). Hagfish and lancelet fibrillar collagens reveal that type II collagen-based cartilage evolved in stem vertebrates. Proceedings of the National Academy of Sciences USA. 103: 16829-16833.
Freitas, R. Zhang, G. and Cohn, M. J. (2006). Evidence that mechanisms of fin development evolved in the midline of early vertebrates. Nature, 442:1033-1037.
Freitas, R., Zhang, G. and Cohn, M. J. (2007). Biphasic Hoxd gene expression in shark paired fins reveals an ancient origin of the distal limb domain. PLoS One 2:e754,1-10.
Cohn, M.J. (2002). Lamprey Hox genes and the origin of jaws. Nature. 416:386-387
