The intensity of the BMP signal is determined by cell surface receptors that phosphorylate Smad1/5/8 at the C-terminus. axes. The positional information produced by these signal gradients are seamlessly integrated in each individual embryo. A classic example of the self-regulating nature of this patterning integration is demonstrated by cutting a Vamp5 blastula stage embryo in half along its D-V axis: the two halves go on to ultimately form perfectly matching twins. How signals emanating TG 100713 from distant points of a morphogenetic field can communicate to each cell within the field when to differentiate proliferate or die is key to understanding how embryos tissues and organs are patterned. Recent advances have begun to address this issue with Smad1 identified as a central candidate in this process. Smad1 has been recently shown to be at the crossroads of the BMP/BMP receptor the FGF/MAPK and Wnt/GSK3 signaling pathways which are integrated through specific phosphorylations in this transcription factor. Here we review how positional information provided by D-V and A-P growth factor gradients in the developing embryo are integrated at the level of Smad1/5/8. Global positioning in the developing embryo Two important gradients signal in the developing embryo acting together as a global positioning system for the early embryonic morphogenetic field (Figure 1). These morphogen gradients determine the D-V and A-P axes providing Cartesian coordinates for the body plan that determines where subsequent self-regulating organ morphogenetic fields for parts such as eyes brain and limbs are placed at later stages of development [1]. Figure 1 gastrula stage embryo showing some of the main morphogenetic fields that form along the D-V (BMP) and TG 100713 A-P (Wnt) axes. These fields are considered self-regulating (as is the early blastula embryo as well) because they can be cut in half and regenerate … The D-V axis is established by BMP (bone morphogenetic protein) signals which subdivide the ectoderm into central nervous system neural crest and epidermis. In the mesoderm from dorsal to ventral notochord somite and intermediate (kidney) and lateral (body wall) mesodermal tissues are generated by the BMP gradient. Thus the D-V system regulates the initial histotypic differentiations of the vertebrate embryo. An elaborate system of extracellular protein-protein interactions regulates this patterning gradient. Chordin a secreted BMP antagonist is expressed in the dorsal region of the vertebrate embryo during the gastrula stage while on the opposite side at the ventral pole BMPs are expressed at high levels [2 3 4 BMPs activate their receptors (BMPR) which are transmembrane serine/threonine kinases and these in turn phosphorylate the transcription factor Smad1 at its C-terminal serines. Once phosphorylated Smad1 translocates into TG 100713 the nucleus and activates or represses BMP-responsive genes [5 6 BMP antagonists such as Chordin and Noggin inhibit C-terminal phosphorylation of Smad1 and induce the ectoderm to adopt a neural fate [7] while high ventral BMP levels ensure that the ectoderm differentiates into an epidermal cell fate [8]. These two opposing ventral and dorsal signaling centers provide the basis for D-V patterning in embryos such as and zebrafish by controlling the intensity of the pSmad1Cter signal a cell will receive. D-V pattern is self-regulating because the dorsal and ventral signaling centers are under opposite transcriptional control [2 9 Dorsal genes are transcribed at low Smad1/5/8 activity levels. A decrease in BMP levels triggers TG 100713 transcription of a dorsal BMP (called ADMP) [9]. Ventral center genes are activated by Smad1 and include BMP4/7 and an enzyme of the Tolloid family of zinc metalloproteinases called Xolloid-related that degrades Chordin liberating BMP and ADMP for signaling [2 3 At high BMP levels Sizzled a competitive inhibitor of Tolloids is transcribed in and zebrafish increasing the stability of the BMP antagonist Chordin (see figure 4 below) [10 11 In addition at high BMP levels two BMP-binding proteins called Bambi (BMP and Activin Membrane-Bound Inhibitory Protein) [12] and Crossveinless-2 [13] are TG 100713 produced further dampening the.