Probes for INS

Grem1, an antagonist of bone morphogenetic proteins, plays a key role in embryogenesis. A highly specific temporospatial gradient of Grem1 and BMP signalling is critical to normal lung, kidney and limb development. Grem1 levels are increased in renal fibrotic conditions including acute kidney injury, diabetic nephropathy, chronic allograft nephropathy and immune glomerulonephritis. A small number of grem1-/- whole body knockout mice on a mixed genetic background (8 %) are viable, with a single, enlarged left kidney and grossly normal histology. Grem1-/- mice displayed mild renal dysfunction at 4 wk, which recovered by 16 wk. Tubular epithelial specific targeted deletion of Grem1 (Grem1-TEC-/-) mice displayed a milder response in both the acute injury and recovery phase of the folic acid model. Grem1-TEC-/- mice had smaller increases in indices of kidney damage compared to wild-type. In the recovery phase of the folic acid model, associated with renal fibrosis, Grem1-TEC-/- mice displayed reduced histological damage and an attenuated fibrotic gene response compared to wild-type controls. Together, these data demonstrated that Grem1 expression in the tubular epithelial compartment plays a significant role in the fibrotic response to renal injury in vivo.

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.