Martin J. Cohn, University of Florida: "Fins, limbs and genitalia: from evolutionary origins to congenital malformations"
Apr 29 2008, 11:00 am
Distinguished Lecture Series Guest Speaker:
Martin J. Cohn
Department of Biology
University of Florida
Date & Time:Tuesday April 29, 2008
Development of paired appendages -- fins and limbs -- was a major innovation during vertebrate evolution. The origin of paired appendages involved the initiation of new axes of outgrowth, three-dimensional patterning of these novel structures, and differentiation of a complex yet integrated suite of tissues. The fossil record indicates that paired fins, the homologs of paired limbs, were preceded in evolution by the evolution of median (unpaired) fins along the dorsal and ventral midlines. We have investigated median fin development in sharks, which have both median and paired fins, and in lampreys, which diverged from the lineage leading to jawed vertebrates prior to the evolution of paired fins. Our studies have uncovered a surprising origin for the developmental genetic program that regulates limb development. Sometime after the transition of fins to limbs, tetrapods evolved another appendage, the external genitalia. Like limb development, formation of external genitalia requires tight coordination of proximodistal outgrowth and three-dimensional patterning. Patterning of the external genitalia involves re-deployment of the highly conserved gene networks that operate during limb development. In addition, these processes must be coordinated with tubular morphogenesis to form the penile urethra. Congenital malformations of the penis arise when these processes are disrupted. The most common penile anomaly is hypospadias, which is characterized by a ventral failure of urethral tube closure. Affected children can have mislocalized, multiple or oversized urethral openings, and males with severe hypospadias are born with ambiguous genitalia. In the US, the frequency of hypospadias doubled, without explanation, from 1968 to 1993, and now affects 1:250 live births. Despite this, there is a relatively poor understanding of the cell types that give rise to, and the molecular mechanisms that control morphogenesis of, external genitalia. A major focus of our lab is the identification of the signals that control outgrowth of the external genitalia and urethral tube formation. We have identified a new signaling region, the urethral epithelium, and found that its signaling activity is mediated by the Sonic hedgehog (Shh) protein. Shh has multiple roles in external genital development, and disruption of Shh function at different stages results in different classes of genital defect. In addition, these experiments are uncovering how interactions between locally-acting gene networks and systemically-acting steroid hormones are involved in sexual differentiation of the genitalia. Disruption of these interactions by environmental contaminants can lead to hypospadias, and we are working towards identifying the genomic targets of these factors in the developing genitalia.