Developmental Biology, Experimental Evolutionary Biology
University of Florida
Dr. Cohn is also a professor of molecular genetics and microbiology and a professor of biology at the University of Florida, Gainesville.
Marty Cohn studies how appendages such as limbs and genitalia develop in vertebrate embryos. He combines developmental genetics of the mouse with comparative development of a wide range of organisms to understand the relationships between development and evolution.
Marty Cohn's laboratory at the University of Florida resembles a zoological garden of embryos. In addition to traditional model organisms such as mice and chicks, there are pythons, sharks, alligators, ostriches, ducks, turtles, lampreys, squid, and horseshoe crabs. Cohn's group uses this assortment of vertebrate and invertebrate creatures to study the development of appendages—specifically, limbs and genitalia. Cohn wants to identify the genetic mechanisms that determine how these appendages obtain their distinctive forms. Moreover, by comparing the development of animals at different positions on the evolutionary tree, he can gain insights into how the genes that orchestrate embryonic development have shaped evolution and vice versa.
Cohn started on his research path as a graduate student in biological anthropology at Kent State University, where he was interested in why digit proportions differ among primates. Soon his attention shifted from why anatomical patterns change to how such changes arise during evolution, and so he finished his master's in anthropology and began a Ph.D. in developmental biology at University College London. There, Cohn studied the molecular control of limb development in chick embryos. He discovered that a single molecule—a Fibroblast growth factor (Fgf)—was a master switch for limb formation. Exploring further, he found that an ancient family of transcription factors called Hox genes was involved in determining the positions of arms and legs. Cohn began to wonder whether tweaking these mechanisms could result in the evolutionary changes that originally sparked his interest in biology.
Cohn has since investigated the developmental causes of some of the biggest breakthroughs in vertebrate evolution—the origin of cartilage, the emergence of fins and jaws, and the modification of fins into limbs. He has also studied how limbs have been lost in animals such as snakes and whales. While these anatomical forms evolved over millions of years, change can happen much more rapidly. The incidence of human birth defects involving the external genitalia has more than doubled in a few decades, for example. Cohn wants to know why.
Compared to what's been learned about limbs, our basic knowledge of external genitalia formation has been woefully inadequate, says Cohn. Yet he has always been struck by the similarities between budding limbs and the developing genital tubercle, the embryonic structure that gives rise to male and female genitalia. "The embryo has to solve many of the same problems to form limbs and genitalia," he says.
In developing limbs, a specialized population of cells acts as an organizing center—for example, telling cells at the top of the limb to form a thumb and those at the bottom to make a pinky finger. Using microsurgical manipulations and molecular genetics, Cohn's lab identified the organizing center of the genital tubercle and showed that it patterns the genitalia using the same signaling molecule—a protein called Sonic hedgehog—that operates in the limb bud.
But external genitalia are structurally more complex than limbs. In addition to outgrowth and three-dimensional patterning, developing genitalia must also form a urethral tube. It is this process that is disrupted in the most common birth defect of the genitourinary tract, a condition called hypospadias that now affects 1 in 250 live births in the United States. "In hypospadias, the urethral tube either fails to close or it closes incompletely," Cohn explains.
By carrying out transcriptional profiling of specific cell populations in the embryonic genitalia of mice, Cohn's lab constructed a molecular map of the genital tubercle. By studying mice with targeted gene mutations, they zeroed in on the role of a fibroblast growth factor receptor (FgfR) in closure of the urethral tube. Disrupting FgfR2 function produced a mouse with an open urethral tube—the same defect that occurs in human hypospadias. His team demonstrated that the masculinizing hormone androgenwas needed to transcribe the Fgf receptor in the genital tubercle of mouse embryos. If androgen signaling is too weak, the Fgf receptor fails to switch on and the mice develop a urethral tube defect. This is the first direct evidence, says Cohn, of genes in the developing tubercle taking cues from a circulating steroid hormone.
This reinforces his view that the rise in genitourinary birth defects is not primarily due to defective genes. Cohn believes that the more likely cause is transient exposure in utero to environmental contaminants called endocrine disrupting chemicals (EDCs), residues from a variety of widely used agricultural and industrial products that interfere with the body's hormones. A mutation couldn't move through the human population fast enough to explain the rise, says Cohn. Instead, embryos are being exposed to EDCs during a critical developmental window, briefly disrupting the signaling that controls urethral formation. "The mother just happens to come in contact with an EDC at the wrong time," he says. To understand how EDCs interfere with embryonic development, Cohn's lab is now scanning the entire genome for developmental genes that are responsive to these pervasive chemicals.
"We're trying to address a problem that lies at the interface of genetics, evolution, and ecotoxicology," Cohn adds. "But I think that the most interesting questions in biology are the ones that transcend disciplinary boundaries."