Zhang Y, etal., Development. 2016 Jan 15;143(2):356-66. doi: 10.1242/dev.125591. Epub 2015 Dec 17.
The developing lens is a powerful system for investigating the molecular basis of inductive tissue interactions and for studying cataract, the leading cause of blindness. The formation of tightly controlled cell-cell adhesions and cell-matrix junctions between lens epithelial (LE) cells, between len
s fiber (LF) cells, and between these two cell populations enables the vertebrate lens to adopt a highly ordered structure and acquire optical transparency. Adhesion molecules are thought to maintain this ordered structure, but little is known about their identity or interactions. Cysteine-rich motor neuron 1 (Crim1), a type I transmembrane protein, is strongly expressed in the developing lens and its mutation causes ocular disease in both mice and humans. How Crim1 regulates lens morphogenesis is not understood. We identified a novel ENU-induced hypomorphic allele of Crim1, Crim1(glcr11), which in the homozygous state causes cataract and microphthalmia. Using this and two other mutant alleles, Crim1(null) and Crim1(cko), we show that the lens defects in Crim1 mouse mutants originate from defective LE cell polarity, proliferation and cell adhesion. Crim1 adhesive function is likely to be required for interactions both between LE cells and between LE and LF cells. We show that Crim1 acts in LE cells, where it colocalizes with and regulates the levels of active beta1 integrin and of phosphorylated FAK and ERK. The RGD and transmembrane motifs of Crim1 are required for regulating FAK phosphorylation. These results identify an important function for Crim1 in the regulation of integrin- and FAK-mediated LE cell adhesion during lens development.
Crim1 is a transmembrane protein that regulates the bioavailability of growth factors such as VEGFA. Crim1(KST264)(/)(KST264) hypomorphic mice develop renal disease characterized by glomerular cysts and loss of endothelial i
ntegrity, progressing to peritubular and pericystic fibrosis. Peritubular capillary endothelial cells display morphological changes as well as detachment from the basement membrane. In this study, gene expression profiling of CD31(+) endothelial cells isolated from Crim1(KST264)(/)(KST264) kidneys showed up-regulation of transcripts associated with fibrosis (Col3a1, Loxl1), endothelial dysfunction (Abp1, Dcn, Lcn2), biomarkers of renal damage (Lcn2, Havcr1/Kim1) as well as evidence for a TGFbeta1/TNF-associated inflammatory process. To determine whether the aberrant endothelium may in part contribute to the fibrogenic process, Tie2Cre-DsRed lineage tracing was undertaken in Crim1(KST264/KST264) mice. Approximately 31% of de novo alphaSMA(+) myofibroblasts detected within the tubulointerstitium were Tie2(+) DsRed(+) . However, 5.3% were F4/80(+) DsRed(+) , indicating a small population of myofibroblasts of monocytic rather than endothelial origin. In contrast, only 12% of myofibroblasts located around glomerular cysts were Tie2(+) DsRed(+) , with 7.7% being monocyte-derived (F4/80(+) DsRed(+) ). Collectively, this model supports the involvement of endothelial cells/monocytes in fibrosis within the tubulointerstitium, but also the heterogeneity of the fibrotic process even within distinct regions of the same kidney.
CRIM1 is a member of the bone morphogenetic protein (BMP) antagonists; however, the role of CRIM1 in controlling cancer cell behavior remains unknown. This study investigated its function in the A549 cell line in vitro. The
results show that treating cells with CRIM1 peptide could increase the migration and adhesion of A549. Consistently, silencing the CRIM1 expression decreased the migration and adhesion of A549. Furthermore, the CRIM1 protein expression was increased in A549 which were treated with transforming growth factor beta 1 to induced EMT. However, CRIM1 peptide treatment could increase the expression of N-CAD and E-CAD expression. Finally, overexpression of the oncogene YAP1 resulted in an up-regulation of the CRIM1 expression in A549, suggesting that CRIM1 was a target of the Hippo pathway. These observations provide evidence for the first time that CRIM1 plays a role in cancer cells by enhancing the migration and adhesion and increasing the expression of N-CAD and E-CAD.
