Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) {beta}3 and is essential for mouse palatogenesis [Cell Biology]

Glycoprotein A repetitions predominant (GARP) (encoded by the Lrrc32 gene) plays important roles in cell-surface docking and activation of TGF-beta. However, GARP role in organ development in mammalian system 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 hours 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 (MEE) cells of the palatal shelf of GARP-KO embryos at day 14.5 (E14.5), indicating a defect in the TGF-beta 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 the GARP-KO mice phenocopied TGF-beta 3-KO mice, although GARP has not been previously suggested to interact with TGF-beta 3. We found that GARP and TGF-beta 3 co-localize in MEE cells at E14.5. In vitro studies confirmed that GARP and TGF-beta 3 directly interact and that GARP is indispensable for the surface expression of membrane-associated latent TGF-beta 3. Our findings indicate that GARP is essential for normal morphogenesis of the palate and demonstrate that GARP plays a crucial role in regulating TGF-beta 3 signaling during embryogenesis. In conclusion, we have uncovered a novel function of GARP in positively regulating TGF-beta 3 activation and function.

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