Evolution of Vertebrate Limb Development
Our lab aims to understand the molecular genetic mechanisms responsible for the evolutionary diversification 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. We are investigating the developmental genetic and genomic 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 comparative approaches to developmental biology, genetics, and genomics, in which the molecular control of embryonic development is studied in a range of organisms that sit at key phylogenetic positions.
Molecular Genetics of External Genitalia 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. These studies focus predominantly on the mouse as a model system, and involve developmental genetics, multi-omics approaches, experimental embryology, and experimental developmental endocrinology 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) specify distinct cell types in the genitourinary tract, (2) control outgrowth and three-dimensional patterning of the genital tubercle, (3) regulate development of the urethral tube, (4) control sexual differentiation of genitourinary organs during embryonic development . 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 form has diversified during tetrapod evolution.
GUDMAP
GenitoUrinary Development Molecular Anatomy Project
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 GUDMAP 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 specialized cell types in the urethra and external genitalia , 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 are achieved by integration of single-cell and bulk RNA sequencing, three-dimensional imaging technology (e.g., nano-computed tomography) and single-molecule multiplexed in situ gene expression analyses.
The roles of our laboratory in GUDMAP 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 specialized cell types in the urethra and external genitalia , 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 are achieved by integration of single-cell and bulk RNA sequencing, three-dimensional imaging technology (e.g., nano-computed tomography) and single-molecule multiplexed in situ gene expression analyses.
