Loss of Bicc1 impairs tubulomorphogenesis of cultured IMCD cells by disrupting E-cadherin-based cell-cell adhesion

Abstract

Bicaudal-C (Bic-C) gene was originally discovered in Drosophila melanogaster. The gene product Bic-C is thought to serve as an RNA-binding molecule targeting diverse proteins at the posttranscriptional level. Recent research has shown this gene to be conserved in many species, from Caenorhabditis elegans to humans. Disruption of this protein can disturb the normal migration direction of the anterior follicle cell of Drosophila oocytes, while mutation of a mouse Bicc1 (a mouse homologue of Bic-C) results in phenotypes mimicking human hereditary polycystic kidney disease (PKD). However, the cellular function of Bicc1 gene products in mammalian system remains largely unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which Bicc1 was silenced by short hairpin RNA inhibition (shRNA). We show that inhibition of Bicc1 disrupted normal tubulomorphogenesis and induced cystogenesis of IMCD cells grown in three dimensional cultures. To determine what factors contributed to the defect, we systematically examined biological changes of Bicc1-silenced IMCD cells. We found that the cells had significant defects in E-cadherin-based cell-cell adhesion, along with abnormalities in actin cytoskeleton organization, cell-extracellular matrix interactions, cell proliferation, and apoptosis. These findings suggest that lack of Bicc1 leads to disruption of normal cell-cell junctions, which in turn impedes establishment of epithelial polarity. These cellular defects may initiate abnormal tubulomorphogenesis and cystogenesis of IMCD cells grown in vitro. The observation of aberrant cellular behaviors in Bicc1-silenced IMCD cells reveal functions for Bicc1 in renal epithelial cells and provides insight into a potential pathogenic mechanism of polycystic kidney disease.

Specificity factors in cytoplasmic polyadenylation

“…The Bicaudal C homolog BICC1 is linked to polycystic kidney disease in zebrafish, Xenopus , mouse and human, this is caused by defects in epithelial morphogenesis . CPEB1 deficiency also causes epithelial defects in the breast tissue of mice .…”

“…The Bicaudal C homolog BICC1 is linked to polycystic kidney disease in zebrafish, Xenopus, mouse and human, [290][291][292] this is caused by defects in epithelial morphogenesis. [292][293][294][295] CPEB1 deficiency also causes epithelial defects in the breast tissue of mice. 296 These observations complement the long established localization of the polyadenylation factor SYMPK at tight junctions, 297,298 and suggest a potential function for local translation mediated by cytoplasmic polyadenylation in the morphogenesis of epithelia.…”

Loss of Polycystin-1 Inhibits Bicc1 Expression during Mouse Development

“…Our previous results showed that the inhibition of Bicc1 disrupts normal tubulomorphogenesis and induces the cystogenesis of IMCD cells grown in three-dimensional culture [24]. These cells also have a significant defect in E-cadherin-based cell-cell adhesion, along with abnormalities in actin cytoskeletal organization, cell-extracellular matrix interactions, ciliogenesis, and cell proliferation/apoptosis.…”

Transcriptome-wide Landscape of Pre-mRNA Alternative Splicing Associated with Metastatic Colonization

“…BICC1 and RBM47 had dramatically decreased expression levels in GS689.Li ( BICC1 : fold change=7, FDR=3.24e-84; RBM47 : fold change=67, FDR=3.42e-261; see Figure 4B). Interestingly, prior work revealed that loss of mouse Bicc1 disrupts E-cadherin-based cell-cell adhesion and epithelial cell polarity (74). RBM47 was recently found to inhibit breast cancer re-initiation and growth and act as a suppressor of breast cancer metastasis (75).…”