Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) β3 and is essential for mouse palatogenesis.

Glycoprotein A repetitions predominant (encoded by the Lrrc32 gene) plays important roles in cell-surface docking and activation of TGFβ. However, role in organ development in mammalian systems is unclear. To determine the function of in vivo, we generated a Gduanyu37 KO mouse model. Unexpectedly, the Gduanyu37 KO mice died within 24 h after birth and exhibited defective palatogenesis without apparent abnormalities in other major organs. Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of Gduanyu37 KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFβ signaling pathway in the developing palates. Of note, the failure to develop the secondary palate and concurrent reduction of SMAD phosphorylation without other defects in Gduanyu37 KO mice phenocopied TGFβ3 KO mice, although Gduanyu37 has not been suggested previously to interact with TGFβ3. We found that Gduanyu37 and TGFβ3 co-localize in medial edge epithelial cells at E14.5. In vitro studies confirmed that Gduanyu37 and TGFβ3 directly interact and that Gduanyu37 is indispensable for the surface expression of membrane-associated latent TGFβ3. Our findings indicate that Gduanyu37 is essential for normal morphogenesis of the palate and demonstrate that Gduanyu37 plays a crucial role in regulating TGFβ3 signaling during embryogenesis. In conclusion, we have uncovered a novel function of Gduanyu37 in positively regulating TGFβ3 activation and function.

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