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FoxK mediates TGF-beta signalling during midgut differentiation in flies.

Casas-Tinto S, Gomez-Velazquez M, Granadino B, Fernandez-Funez P - J. Cell Biol. (2008)

Bottom Line: Genet.This regulatory activity does not require direct labial activation by the TGF-beta effector Mad.Thus, we propose that the combined activity of the TGF-beta target genes FoxK and Dfos is critical for the direct activation of lab in the endoderm.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA. scasas@cnio.es

ABSTRACT
Inductive signals across germ layers are important for the development of the endoderm in vertebrates and invertebrates (Tam, P.P., M. Kanai-Azuma, and Y. Kanai. 2003. Curr. Opin. Genet. Dev. 13:393-400; Nakagoshi, H. 2005. Dev. Growth Differ. 47:383-392). In flies, the visceral mesoderm secretes signaling molecules that diffuse into the underlying midgut endoderm, where conserved signaling cascades activate the Hox gene labial, which is important for the differentiation of copper cells (Bienz, M. 1997. Curr. Opin. Genet. Dev. 7:683-688). We present here a Drosophila melanogaster gene of the Fox family of transcription factors, FoxK, that mediates transforming growth factor beta (TGF-beta) signaling in the embryonic midgut endoderm. FoxK mutant embryos fail to generate midgut constrictions and lack Labial in the endoderm. Our observations suggest that TGF-beta signaling directly regulates FoxK through functional Smad/Mad-binding sites, whereas FoxK, in turn, regulates labial expression. We also describe a new cooperative activity of the transcription factors FoxK and Dfos/AP-1 that regulates labial expression in the midgut endoderm. This regulatory activity does not require direct labial activation by the TGF-beta effector Mad. Thus, we propose that the combined activity of the TGF-beta target genes FoxK and Dfos is critical for the direct activation of lab in the endoderm.

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Dpp signaling events in the endoderm. Diffusion of Dpp from the visceral mesoderm (VM) activates its receptor, Tkv, in the underlying endoderm (EN), which leads to the formation of transcriptionally active Mad–Med complexes (1). Mad and Med then regulate the expression of FoxK and Dfos, which are critical for the initiation of lab expression by binding to its promoter (2, large boxes). Mad may contribute to lab activation, whereas Mad and Lab are necessary for lab maintenance. Finally, Lab controls the expression of target genes critical for copper cell differentiation (3).
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fig9: Dpp signaling events in the endoderm. Diffusion of Dpp from the visceral mesoderm (VM) activates its receptor, Tkv, in the underlying endoderm (EN), which leads to the formation of transcriptionally active Mad–Med complexes (1). Mad and Med then regulate the expression of FoxK and Dfos, which are critical for the initiation of lab expression by binding to its promoter (2, large boxes). Mad may contribute to lab activation, whereas Mad and Lab are necessary for lab maintenance. Finally, Lab controls the expression of target genes critical for copper cell differentiation (3).

Mentions: It has been shown previously that Mad binds the regulatory region of lab and is required for lab expression (Marty et al., 2001). We wondered, though, if FoxK and Dfos could activate lab in the endoderm in the absence of Mad input. To inhibit Dpp signaling, we overexpressed tkvDN in the endoderm, which prevented the accumulation of phosphorylated (activated) Mad (pSmad; Fig. 8, I and O) and Lab (Fig. 7 G) in the midgut. Next, we tested the ability of FoxK alone to restore Lab expression in embryos coexpressing tkvDN. In the absence of Dpp activity, FoxK was not enough to induce lab expression in parasegment 7 (Fig. 8 M and N). We then created embryos overexpressing tkvDN, FoxK, and Dfos in the endoderm. Strikingly, Lab expression was restored in the midgut of these embryos, even though pSmad was undetectable in the endoderm (Fig. 8, P–R). Moreover, these embryos formed a constriction in the absence of pSmad (Fig. 8 P, arrow), which demonstrated that forced expression of FoxK and Dfos in the endoderm could bypass the Mad-dependent activation of lab. Thus, lab expression in the midgut endoderm depends on the direct activity of FoxK and Dfos, suggesting that a new, sequential signaling mechanism controls Dpp-dependent lab expression during endoderm development (Fig. 9).


FoxK mediates TGF-beta signalling during midgut differentiation in flies.

Casas-Tinto S, Gomez-Velazquez M, Granadino B, Fernandez-Funez P - J. Cell Biol. (2008)

Dpp signaling events in the endoderm. Diffusion of Dpp from the visceral mesoderm (VM) activates its receptor, Tkv, in the underlying endoderm (EN), which leads to the formation of transcriptionally active Mad–Med complexes (1). Mad and Med then regulate the expression of FoxK and Dfos, which are critical for the initiation of lab expression by binding to its promoter (2, large boxes). Mad may contribute to lab activation, whereas Mad and Lab are necessary for lab maintenance. Finally, Lab controls the expression of target genes critical for copper cell differentiation (3).
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2600746&req=5

fig9: Dpp signaling events in the endoderm. Diffusion of Dpp from the visceral mesoderm (VM) activates its receptor, Tkv, in the underlying endoderm (EN), which leads to the formation of transcriptionally active Mad–Med complexes (1). Mad and Med then regulate the expression of FoxK and Dfos, which are critical for the initiation of lab expression by binding to its promoter (2, large boxes). Mad may contribute to lab activation, whereas Mad and Lab are necessary for lab maintenance. Finally, Lab controls the expression of target genes critical for copper cell differentiation (3).
Mentions: It has been shown previously that Mad binds the regulatory region of lab and is required for lab expression (Marty et al., 2001). We wondered, though, if FoxK and Dfos could activate lab in the endoderm in the absence of Mad input. To inhibit Dpp signaling, we overexpressed tkvDN in the endoderm, which prevented the accumulation of phosphorylated (activated) Mad (pSmad; Fig. 8, I and O) and Lab (Fig. 7 G) in the midgut. Next, we tested the ability of FoxK alone to restore Lab expression in embryos coexpressing tkvDN. In the absence of Dpp activity, FoxK was not enough to induce lab expression in parasegment 7 (Fig. 8 M and N). We then created embryos overexpressing tkvDN, FoxK, and Dfos in the endoderm. Strikingly, Lab expression was restored in the midgut of these embryos, even though pSmad was undetectable in the endoderm (Fig. 8, P–R). Moreover, these embryos formed a constriction in the absence of pSmad (Fig. 8 P, arrow), which demonstrated that forced expression of FoxK and Dfos in the endoderm could bypass the Mad-dependent activation of lab. Thus, lab expression in the midgut endoderm depends on the direct activity of FoxK and Dfos, suggesting that a new, sequential signaling mechanism controls Dpp-dependent lab expression during endoderm development (Fig. 9).

Bottom Line: Genet.This regulatory activity does not require direct labial activation by the TGF-beta effector Mad.Thus, we propose that the combined activity of the TGF-beta target genes FoxK and Dfos is critical for the direct activation of lab in the endoderm.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA. scasas@cnio.es

ABSTRACT
Inductive signals across germ layers are important for the development of the endoderm in vertebrates and invertebrates (Tam, P.P., M. Kanai-Azuma, and Y. Kanai. 2003. Curr. Opin. Genet. Dev. 13:393-400; Nakagoshi, H. 2005. Dev. Growth Differ. 47:383-392). In flies, the visceral mesoderm secretes signaling molecules that diffuse into the underlying midgut endoderm, where conserved signaling cascades activate the Hox gene labial, which is important for the differentiation of copper cells (Bienz, M. 1997. Curr. Opin. Genet. Dev. 7:683-688). We present here a Drosophila melanogaster gene of the Fox family of transcription factors, FoxK, that mediates transforming growth factor beta (TGF-beta) signaling in the embryonic midgut endoderm. FoxK mutant embryos fail to generate midgut constrictions and lack Labial in the endoderm. Our observations suggest that TGF-beta signaling directly regulates FoxK through functional Smad/Mad-binding sites, whereas FoxK, in turn, regulates labial expression. We also describe a new cooperative activity of the transcription factors FoxK and Dfos/AP-1 that regulates labial expression in the midgut endoderm. This regulatory activity does not require direct labial activation by the TGF-beta effector Mad. Thus, we propose that the combined activity of the TGF-beta target genes FoxK and Dfos is critical for the direct activation of lab in the endoderm.

Show MeSH
Related in: MedlinePlus