Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) 3 and is essential for mouse palatogenesis

Glycoprotein A repetitions predominant (GARP) (encoded by the Lrrc32 gene) plays important roles in cell-surface docking and activation of TGF. However, GARP's role in organ development in mammalian systems is unclear. To determine the function of GARP in vivo, we generated a GARP KO mouse model. Unexpectedly, the GARP 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 GARP KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGF signaling pathway in the GARP-null developing palates. Of note, the failure to develop the secondary palate and concurrent reduction of SMAD phosphorylation without other defects in GARP KO mice phenocopied TGF3 KO mice, although GARP has not been suggested previously to interact with TGF3. We found that GARP and TGF3 co-localize in medial edge epithelial cells at E14.5. In vitro studies confirmed that GARP and TGF3 directly interact and that GARP is indispensable for the surface expression of membrane-associated latent TGF3. Our findings indicate that GARP is essential for normal morphogenesis of the palate and demonstrate that GARP plays a crucial role in regulating TGF3 signaling during embryogenesis. In conclusion, we have uncovered a novel function of GARP in positively regulating TGF3 activation and function.