Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects

Area of Science:

• Genetics
• Developmental Biology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is linked to high polycystin-1 expression.
• Overexpression of polycystin-1 in mice causes renal cysts, but its necessity for cystogenesis is unknown.

Purpose of the Study:

• To investigate the role of polycystin-1 in cyst formation and skeletal development.
• To compare the phenotypes of null Pkd1 mutants with existing truncation mutants.

Main Methods:

• Generation of a targeted mouse mutant with a null mutation in Pkd1.
• Phenotypic characterization of null homozygotes, del34 homozygotes, and heterozygotes.
• Comparison of cyst formation and skeletal abnormalities between mutant lines.

Main Results:

• Null Pkd1 homozygotes exhibit aggressive renal and pancreatic cystic disease, similar to del34 homozygotes.
• Both homozygous mutants display polyhydramnios, hydrops fetalis, spina bifida occulta, and osteochondrodysplasia.
• Heterozygotes develop adult-onset pancreatic disease; del34 homozygotes produce mutant polycystin-1.

Conclusions:

• Loss of polycystin-1 function is sufficient to cause cyst formation in kidneys and pancreas.
• Polycystin-1 is essential for normal skeletogenesis, impacting chondrocyte development.
• These findings highlight polycystin-1's critical roles in epithelial and skeletal development.