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

Abstract

Glycoprotein A repetitions predominant (GARP) (encoded by the 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 , 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. 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.

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

“…Garp-deficient mice do not exhibit apparent abnormalities in major organs; however, they show defective palatogenesis and die within 24 hours after birth [211]. Interestingly, the failure to develop the secondary palate and reduction of Smad2 phosphorylation without other defects in Garp-deficient mice are similar to the phenotype of Tgfb3-null mice.…”

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

“…However, further study is necessary to clarify how GARP is regulated by TLR pathways. GARP is known to bind to TGF-β1, TGF-β2, and TGF-β3 (45). There is evidence that resting B cells express higher levels of TGF-β3 than activated B cells and are able to expand Treg populations in a TGF-β3-dependent mechanism (83).…”

“…We developed an inducible GARP OE mouse model using the "Flexible Accelerated STOP TetO knockin system" (Ingenious Targeting Laboratory) (86). Development of the GARP-FAST mouse model has been described previously (45). GARP OE was induced with doxycycline (50 μg/ml; MilliporeSigma) in 1% sucrose drinking water.…”

“…In order to understand the biological significance of B cell GARP expression, we generated an inducible mouse model to control GARP expression pharmacologically (45). We knocked in a Tet-on trans-acting element to the promoter region of the endogenous GARP gene, Lrrc32.…”

Truncation of TGF-β docking receptor GARP is linked to human disease

“…Glycoprotein-A Repetitions Predominant (GARP), encoded by LRRC32, is a type I transmembrane protein with a large extracellular domain for cell surface docking and activation of all three isoforms of latent TGF-β: TGF-β1, TGF-β2 and TGF-β3. GARP has gained increasing attention due to its important roles in immune tolerance [3] and palatogenesis [4] from mouse genetic studies. Genome-wide association study and targeted next-generation sequencing of 11q13.5 in humans has previously linked missense mutation of GARP to atopic dermatitis [5].…”