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Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice.

ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) are some of the most common developmental defects and have a complicated etiology, indicating an interaction of (epi-) genetic and environmental factors. Single gene mutations and copy number variations (CNVs) do not explain most cases of CAKUT, and simultaneous contributions of more than one gene (di-, oligo-, or polygenic effects; i.e., complex genetics) may lead to the pathogenesis of CAKUT. Robo2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. Gen1 is a candidate gene associated with CAKUT because of its important role in early metanephric development in mice. We established a mouse model with double disruption of Robo2 and Gen1 using a piggyBac transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in Robo2 ^PB/+ Gen1 ^PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2 ^PB/+ Gen1 ^PB/+ mice during the embryonic period. Robo2 and Gen1 exert synergistic effects on mouse kidney development, promoting cell proliferation by activating the GDNF/RET pathway and downstream MAPK/ERK signaling. Our findings provide a disease model for CAKUT as an oligogenic disorder.

SUBMITTER: Li Y

PROVIDER: S-EPMC8766746 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To explore the relationship between miR-373 and the occurrence and development of colorectal cancer. Additionally, it aims to predict the potential cellular signaling pathways and regulatory mechanisms in which miR-373 may be involved and provides a theoretical basis and experimental evidence for the clinical application of miR-373 as a potential biomarker, molecular target, and prognostic indicator in colorectal cancer. Real-time quantitative PCR is used to analyze the expression of miR-373 in human colorectal cancer cell lines and normal human colonic epithelial cells. Further validation of the differential expression of miR-373 in colorectal cancer cell lines is being performed. Biological functions such as cell proliferation, invasion and apoptosis are being detected by MTT, CCK-8, transwell, cell cycle analysis, and flow cytometry experiments to verify the changes in the biological behavior of colon cancer cells after overexpression and interference of miR-373 in SW-480 cells and to explore the effects of miR-373 on cell proliferation, invasion, and apoptosis in colon cancer cells. Proteomic analysis is being conducted on proteins extracted from miR-373 overexpressing SW480 cells, and mass spectrometry is used for protein identification. GO, KEGG, and enrichment analysis are being employed to analyze the significantly differentially expressed proteins. The expression levels of pathway-related proteins are being verified using Western blot. Overexpression of miR-373 increased the invasive and metastatic ability of SW-480 cells; knockdown of miR-373 decreased the invasive and metastatic ability of SW-480 cells. However, there was no statistically significant effect on cell proliferation and apoptosis in SW-480 cells. Proteomic analysis identified 78 differentially expressed proteins based on fold change (FC) > 1.2 and P < 0.05. Annotation of differentially changed proteins revealed that the MAPK signaling pathway, PI3K-Akt signaling pathway, and FAK signaling pathway may play crucial roles in the migration and invasion of colorectal cancer. Western blot analysis showed that overexpression of miR-373 significantly increased the levels of p-ERK1/2 in SW480 cells. miR-373 may activate the ERK/MAPK signaling pathway to promote the invasion and migration of colorectal cancer cells.

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Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice.

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