The BMP signaling and in vivo bone formation

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor beta (TGFbeta) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.     

Stage-specific expression of Smad2 and Smad3 during folliculogenesis

Paracrine and autocrine growth factors can affect many different aspects of ovarian follicle development. Many members of the transforming growth factor beta (TGFbeta) family of growth factors and their receptors are expressed in developing follicles. However, the presence and function of the family of the TGFbeta signaling molecules known as Smads have not been evaluated during follicle development. We have demonstrated that two Smad family members that function as mediators for both activin and TGFbeta are expressed in granulosa cells of preantral follicles but not in large antral follicles. Smad2 expression, but not Smad3 expression, returns in luteal cells. Both Smad2 and Smad3 are translocated to the nucleus of granulosa cells in response to treatment with either TGFbeta or activin. However, Smad2 is more responsive to activin stimulation, and Smad3 is more responsive to TGFbeta stimulation. Stage-specific expression and differing ligand sensitivity of signaling molecules may work together to allow different effects of TGFbeta family ligands using the same signaling pathways over the course of follicular development.     

Signal transduction in early heart development (I): cardiogenic induction and heart tube formation

Heart development begins with the induction of cardiogenic cells from the embryonic mesoderm, followed by the coalescing of these cells into a linear heart tube. Subsequent looping of the heart tube brings the rudimentary atria and ventricles into alignment for further development into the four-chambered heart. Underlying these morphologic events is a complex program of signaling between cells and tissues that orchestrates their participation in heart development. Among these signals are bone morphogenetic proteins, fibroblast growth factors, Wnts, Hedgehog, and members of the transforming growth factor-beta family of signaling molecules. We review here the various properties of these signaling molecules and their signal transduction pathways in hopes of providing a greater appreciation of the molecular events driving heart development.     

TGF-beta signaling in human skeletal and patterning disorders

Members of the transforming growth factor beta (TGF-beta) family of multifunctional peptides are involved in almost every aspect of development. Model systems, ranging from genetically tractable invertebrates to genetically engineered mice, have been used to determine the mechanisms of TGF-beta signaling in normal development and in pathological situations. Furthermore, mutations in genes for the ligands, receptors, extracellular modulators, and intracellular signaling molecules have been associated with several human disorders. The most common are those associated with the development and maintenance of the skeletal system and axial patterning. This review focuses on the mechanisms of TGF-beta signaling with special emphasis on the molecules involved in human disorders of patterning and skeletal development.     

Eph and ephrins in epithelial stem cell niches and cancer

The family of Eph tyrosine kinase receptors is an important part of signaling pathways involved in development, tissue homeostasis and tumorigenesis. Binding and activation of the receptors by their ligands, the ephrins, result in bidirectional signaling into both receptor and ligand expressing cells. Adult stem cell niches and tumors frequently express receptors and ligands, although their function is only beginning to be understood. Thus, Eph receptors and ephrins have become important molecules for understanding basic biological processes as well as tumorigenesis, and are promising targets for potential therapeutic intervention in human disease.     

Eph and ephrins in epithelial stem cell niches and cancer

The family of Eph tyrosine kinase receptors is an important part of signaling pathways involved in development, tissue homeostasis and tumorigenesis. Binding and activation of the receptors by their ligands, the ephrins, result in bidirectional signaling into both receptor and ligand expressing cells. Adult stem cell niches and tumors frequently express receptors and ligands, although their function is only beginning to be understood. Thus, Eph receptors and ephrins have become important molecules for understanding basic biological processes as well as tumorigenesis, and are promising targets for potential therapeutic intervention in human disease.