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PMID:14729481
| Citation |
Dudas, M, Nagy, A, Laping, NJ, Moustakas, A and Kaartinen, V (2004) Tgf-beta3-induced palatal fusion is mediated by Alk-5/Smad pathway. Dev. Biol. 266:96-108 |
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| Abstract |
Cleft palate is among the most common birth defects in humans, caused by a failure in the complex multistep developmental process of palatogenesis. It has been recently shown that transforming growth factor beta3 (Tgf-beta3) is an absolute requirement for successful palatal fusion, both in mice and humans. However, very little is known about the mechanisms of Tgf-beta3 signaling during this process. Here we show that putative Tgf-beta type I receptors, Alk-1, Alk-2, and Alk-5, are all endogenously expressed in the palatal epithelium. Activation of Alk-5 in the Tgf-beta3 (-/-) palatal epithelium is able to rescue palatal fusion, whereas inactivation of Alk-5 in the wild-type palatal epithelium prevents palatal fusion. The effect of Alk-2 is similar, but less pronounced. The induction of fusion by activation of Alk-5 or Alk-2 is stronger in the posterior parts of the palates at the embryonic day 14 (E14), while their activation at E13.5 also restores anterior fusion, reflecting the natural anterior-posterior direction of palate maturation in vivo. We also show that Smad2 is endogenously activated in the palatal midline epithelial seam (MES) during the fusion process. By using a mutant Alk-5 receptor that is an active kinase but is unable to activate Smads, we show that activation of Smad-independent Tgf-beta responses is not sufficient to induce fusion of shelves deficient in Tgf-beta3. Based on these observations, we conclude that the Smad2-dependent Alk-5 signaling pathway is dominant in palatal fusion driven by Tgf-beta3. |
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| Keywords |
Activin Receptors, Type I/physiology; Adenoviridae/genetics; Animals; Base Sequence; Cleft Palate/etiology; DNA Primers; DNA-Binding Proteins/physiology; Genetic Vectors; In Situ Hybridization; Mice; Mice, Knockout; Organ Culture Techniques; Palate/embryology; Protein-Serine-Threonine Kinases; Receptors, Transforming Growth Factor beta/physiology; Reverse Transcriptase Polymerase Chain Reaction; Smad Proteins; Trans-Activators/physiology; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/physiology; Transforming Growth Factor beta3 |
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