Abstract
Glycoprotein A repetitions predominant (GARP) (encoded by the Lrrc32 gene) plays important roles in cell-surface docking and activation of TGFβ. 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 TGFβ 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 TGFβ3 KO mice, although GARP has not been suggested previously to interact with TGFβ3. We found that GARP and TGFβ3 co-localize in medial edge epithelial cells at E14.5. In vitro studies confirmed that GARP and TGFβ3 directly interact and that GARP is indispensable for the surface expression of membrane-associated latent TGFβ3. Our findings indicate that GARP is essential for normal morphogenesis of the palate and demonstrate that GARP plays a crucial role in regulating TGFβ3 signaling during embryogenesis. In conclusion, we have uncovered a novel function of GARP in positively regulating TGFβ3 activation and function.
Highlights
Glycoprotein A repetitions predominant (GARP) plays important roles in cell-surface docking and activation of TGF
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
To determine the GARP function in vivo, we have developed a reversible GARP KO mouse model using the flexible accelerated STOP TetO (FAST) knockin system [30], the GARP FAST
Summary
The homozygous GARP KO mice died within 24 h after birth. The only developmental defect observed in KO mice was a cleft palate, which is identical to Tgfb KO mice [26, 31]. We further performed studies to establish the critical roles of GARP in binding and activating TGF3 and identified a novel role of GARP in TGF3 biogenesis and function
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