27 November 2005

Nature Cell Biology doi:10.1038/ncb1326

The catastrophic consequences of autosomal dominant polycystic kidney disease (ADPKD), are caused by two mutated genes working together to cause abnormal cell proliferation that ultimately leads to renal failure. New results published by Jing Zhou and colleagues in Nature Cell Biology unravel how these mutated genes operate. ADPKD is a hereditary affliction of the kidney affecting 1 in 1000 people.

ADPKD is caused by mutation of either the PC1 or the PC2 gene. These are membrane proteins that interact, and may form a signalling receptor and ion channel complex. Several signalling pathways are influenced by the PC1-PC2 complex, but it has remained unclear how mutation of these genes leads to derailed renal epithelial cell proliferation.

The Zhou group now demonstrates that PC2 associates with the important cell cycle and cell differentiation regulatory protein, Id2. This association prevents entry of Id2 into the cell nucleus, where it normally acts on cell cycle genes. PC1 turns out to be essential for the PC2-Id2 interaction, explaining why loss of either PC1 or PC2 leads to unchecked nuclear accumulation, and therefore derailed activation of the growth promoter Id2, in the kidney cells of ADPKD patients. Reduced Id2 expression in cells from a mouse model of ADPKD normalizes cell proliferation, although it remains to be seen if this prevents further kidney disease. Nevertheless, these data suggest that Id2 inhibition is a promising line of therapeutic intervention for this common and severe kidney disease.

20 November 2005

Nature Cell Biology doi:10.1038/ncb1328

A change in the function of a protein in the cerebral cortex may contribute to the subtle neuronal defects observed in the brains of patients with schizophrenia, according to a paper in the December issue of Nature Cell Biology.

Such small changes in the brain's architecture are thought to be contributing factors in the development of the disease and here Akira Sawa and colleagues find that the DISC1 gene is part of a protein complex that is important for the normal movement of cells within the brain cortex during development.

The DISC1 gene is known to reside near the region of the chromosome which is broken, or 'translocated', in several schizophrenia patients from a particular Scottish pedigree. The gene binds to this complex of factors − dynein, LIS1 and NUDEL − and recruits them to the correct location in the cell. When the mutant form of DISC1 is present, as occurs in some schizophrenia patients, this complex no longer reaches the appropriate location. This complex is known to be important for normal neuronal growth in cell culture and for neuronal cells to migrate normally within the developing cortex. Sawa and colleagues now find that in the absence of DISC1, or when the mutant form of DISC1 is present, cell movement in the developing cerebral cortex is altered.

Together, these results suggest that DISC1 is important for normal formation of the cortex, through its effects on this complex, and that this function may be one reason neuronal development goes awry in a subset of schizophrenia patients.