Background

A fundamental question in developmental biology is how the various tissues and structures of the animal are generated and patterned in characteristic ways. The hematopoietic (blood) and vascular endothelial lineages are the first to arise from nascent mesoderm in the developing mammalian embryo during gastrulation. These cells become organized into the blood islands of the extraembryonic yolk sac and comprise the first circulatory system of the animal. Additional waves of hematopoietic and vasculogenic/angiogenic activity later result in the development of definitive hematopoietic lineages and in the formation of the allantois (a vascular structure which ultimately forms the umbilical vessels of the embryo) and cardiovascular system of the embryo proper. The regulation of these events is poorly understood.

Our research program combines multiple, complementary approaches to study the mechanisms by which cell fate decisions are regulated in stem and progenitor cells with a major focus on embryonic hematopoiesis and vasculogenesis. Although adult bone marrow, peripheral blood, and cord blood currently serve as sources of stem cells for treatment of genetic and malignant diseases, the developmental origin of hematopoietic stem cells remains unclear. At least some of the processes that control the early tissue development may be recapitulated during tissue regeneration (and stem cell activation) in damaged or diseased organs of the adult. Therefore, regulatory molecules identified through studies of basic embryology may provide important clues about how to modulate stem cell behavior and facilitate isolation of various progenitor/precursor cells for therapeutic purposes.

A more recent interest in the lab is the regulation of patterning and morphogenesis of endodermal (e.g., gut, liver, pancreas, etc.) structures in the mouse embryo. We are also involved in a project involving analysis of the developing cardiovascular system of the mouse embryo using in vivo imaging (see below).

Gastrulation Diagram

For the most part, the processes we study occur very early in the developing embryo. This cartoon represents the transformation of the embryo during gastrulation from an epiblast with little morphologically obvious patterning (6.0 days) to one that is beginning to show more obvious structure and differentiation and contains all three germ layers (ectoderm, mesoderm, and endoderm). The VE is visceral or primitive endoderm. It is a secretory tissue that will not contribute directly to the developing animal; however, its function is essential for normal development. For example, we have shown that this layer sends signals to the underlying tissue during formation of the earliest hematopoietic and endothelial cells of the embryo. One signal emitted by the VE is Indian hedgehog (Ihh), a signaling molecule that may function in part through upregulation of another secreted signal in the target tissue: Bone Morphogenetic Protein 4 (Bmp4). The first blood and endothelial cells form in a striking ring of "blood islands" from the extraembryonic mesoderm of the yolk sac. The allantois, a structure that forms at the posterior of the embryo, will contribute to the placenta and will contain the umbilical blood vessels.

Embryo

Mouse embryo inside yolk sac (YS). YS blood vessels are seen.

Embryos

Two transgenic mouse embryos expressing a lacZ reporter gene only in primitive erythroid (red blood) cells. Note ring of blood islands in developing yolk sac.

Embryonic

Structure of the embryonic yolk sac. Note primitive endoderm (VE) and mesoderm layers. Primitive erythroid (EryP) and endothelial cells form from the mesodermal layer. The endodermal layer is ideally positioned to send secreted signals to the mesoderm. Human embryos have YS of analogous structure.