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The polycystic kidney disease 1 gene product modulates Wnt signaling
1Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Abstract:
Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous beta-catenin and stimulates TCF-dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.
Insights
Polycystin, crucial for kidney development, interacts with Wnt signaling. Its C-terminal domain stabilizes beta-catenin and promotes gene transcription, suggesting a role in regulating Wnt signaling during kidney formation.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Wnt signaling and polycystin are vital for kidney development.
- Polycystin mutations cause autosomal dominant polycystic kidney disease by disrupting renal tubular epithelial cell differentiation.
- Polycystin is an integral membrane protein with extracellular and cytoplasmic domains.
Purpose of the Study:
- To investigate the role of the polycystin C-terminal cytoplasmic domain in Wnt signaling.
- To determine if polycystin influences gene transcription related to kidney development.
Main Methods:
- Expression of the polycystin C-terminal cytoplasmic domain in human embryonic kidney cells.
- Measurement of beta-catenin stabilization.
- Assessment of TCF-dependent gene transcription.
- Microinjection of the polycystin C-terminal cytoplasmic domain into zebrafish embryos.
Main Results:
- Expression of the polycystin C-terminal cytoplasmic domain stabilized beta-catenin in kidney cells.
- This domain stimulated TCF-dependent gene transcription.
- Microinjection induced dorsalization in zebrafish, indicating a developmental role.
Conclusions:
- Polycystin's cytoplasmic domain can modulate Wnt signaling.
- This interaction is significant for normal renal development.
- Findings provide insights into polycystic kidney disease pathogenesis.