TGF-β Family Signal Transduction in Drosophila Development: From Mad to Smads

Abstract

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of soluble extracellular proteins that are potent regulators of development in both vertebrates and invertebrates. Drosophila TGF-beta family members include three proteins with homology to vertebrate bone morphogenetic proteins (BMPs): Decapentaplegic (Dpp), Screw, and Glass bottom boat-60A. Genetic studies of Dpp signaling led to the identification of Smad proteins as central mediators of signal transduction by TGF-beta family members. Work in mammalian tissue culture has elucidated a biochemical model for signal transduction, in which activation of receptor serine-threonine kinase activity leads to phosphorylation of specific Smad proteins and translocation of heteromeric Smad protein complexes to the nucleus. Once in the nucleus Smad proteins interact with other DNA binding proteins to regulate transcription of specific target genes. Dissection of Dpp-response elements from genes expressed during embryonic mesoderm patterning and midgut morphogenesis provides important insights into the contributions of Smad proteins and tissue-specific transcription factors to spatial regulation of gene expression. Genetic studies in Drosophila are now expanding to include multiple BMP ligands and receptors and have uncovered activities not explained by the current signal transduction model. Identification of more ligand sequences and demonstration of a functional Drosophila activin-like signal transduction pathway suggest that all TGF-beta signal transduction pathways are present in flies.

Genetic dissection of a stem cell niche: The case of the Drosophila ovary

“…Although we cannot rule out the possibility that the loss of Mad in these cells is compensated for by the presence of other wildtype CpCs in the niche, or that it may take longer than 12-14 days for the removal of Mad to have an effect, taken together our results suggest that the activation of the BMP pathway in the CpCs is not essential for GSC maintenance. These findings exclude a requirement for both gbb and dpp within the CpCs, as all BMP family ligands are believed to be mediated via Mad in Drosophila (Raftery and Sutherland, 1999). Thus, the ability of individual CpCs to perceive BMP ligands is not essential for the maintenance of GSCs with which they are in contact.…”

“…However, other reports found dad-LacZ expressed in some IGS cells but not in the CpCs themselves (Song et al, 2004;Kirilly et al, 2005). To examine if the BMP pathway is functionally required in CpCs for GSC maintenance, we used bab1-Gal4 to drive the formation of mutant clones for the essential Smad effector, Mad (Raftery and Sutherland, 1999). We carefully examined mosaic germaria containing GSCs in contact only with Mad mutant CpCs and found that the lack of Mad expression in these cells 12-14 days after adult eclosion did not have any detectable effect upon GSC renewal ( Fig.…”

“…BMP ligands are detected via the combined action of a type I receptor, encoded by thickveins (tkv) or saxophone, and a type II receptor, encoded by punt (Raftery and Sutherland, 1999). Upon ligand binding, these receptors act to phosphorylate Mad, a Smad transcription factor, which in conjunction with other proteins acts to regulate the expression of target genes.…”

Opposing inputs by Hedgehog and Brinker define a stripe ofhairyexpression in theDrosophilaleg imaginal disc

“…In response to Dpp signaling, an activated form of the Smad transcription factor, Mothers against dpp (Mad), is generated. Mad then binds to a related protein, Medea (Med), and this complex translocates to the nucleus to transcriptionally regulate expression of Dpp target genes (Raftery and Sutherland, 1999;Zimmerman and Padgett, 2000). In a number of cases, it has been observed that the Mad/Med complex binds the enhancers of Dpp target genes and directly activates transcription (Kim et al, 1997;Rushlow et al, 2001;Szuts et al, 1998).…”

Effect of transforming growth factor-β3 on mono and multilayer chondrocytes

“…Different kinds of TGFβs are involved in signal transduction between the extracellular environment and the nucleus. TGF-β 1, 2 and 3 are potent regulators in cellular development (Raftery andSutherland, 2002, Sefat, 2014b). Shah et al (1999) investigated the effect of manipulation of TGF-β on the wound healing process and found that the effects of TGF-β3 is inhibited by the high levels of TGF-β1and 2 from the inflammatory cells in adult tissue.…”