In This Issue

(See article on pages 457–467.)

Among their many unfortunate effects, heavy metals such as cadmium can impair male fertility. Whether oligospermia arises from environmental exposure to cadmium is unclear from epidemiological studies, but male rats treated with this metal reliably decrease their production of mature sperm. Ozawa et al. have found that this response reflects a complex interplay between the developing germ cells and the neighboring somatic cells. Leydig cells, endogenous producers of testosterone and other steroids in the testis, are particularly important in this reaction, because they induce heme oxygenase-1 (HO-1) expression in response to cadmium or other stressors. The enzymes HO-1 and -2 generate CO and biliverdin, starting from the ferric protoporphyrin IX, an iron-complexed form of heme. The authors show that inhibition of HO activity prevents germ cell apoptosis in cadmium-treated animals but that treatment with dichloromethane, which replaces the missing CO, restores this response. Hence, they argue, CO generated within the Leydig cells reaches the developing spermatocytes and causes them to undergo Fas-dependent apoptosis, rather than meiosis. Interestingly, treatment with dichloromethane alone does not cause apoptosis, suggesting that some other aspect of heavy metal toxicity is required for the response. Germ cells apparently die prior to meiosis, since the Fas ligand protein is induced specifically in diploid and tetraploid cells but is not found at heightened levels in the surviving population of haploid spermatids, and the latter cells do not show nuclear condensation or fragmentation, the usual hallmarks of apoptotic cells. The authors suggest that, even in unstressed animals, Leydig cell HO-1 and CO accumulation around germ cells may contribute to a background level of spermatocyte apoptosis in unstressed animals. If so, the same pathway may well be implicated in other forms of oligospermia and male infertility.

(See article on pages 481–489.)

Branching morphogenesis, one of the unifying themes in organogenesis, allows a cluster of epithelial cells to generate a system of branching tubules and ducts, rather than a simple, flat sheet. This event can be recapitulated in 3-dimensional culture systems, when spontaneously formed kidney, lung, or mammary cell aggregates are treated with HGF or any of several other agents. Following up on a recent report that overexpression of the renal epithelial cell membrane protein polycystin-1 stimulates branching of these cells in culture, Nickel and coworkers have now worked out some of the molecular interactions that distinguish this response from the better known pathway induced by HGF. Mutations in the human polycystin-1, or in the interacting protein polycystin-2, are the most frequent cause of polycystic kidney disease, indicating that these two proteins are required for normal kidney cell proliferation and for the structure and function of the renal epithelium. Overexpression of polycystin-1 — or, as the authors now show, of the protein’s polycystin-2-interacting region — leads to greater cell motility, stimulates cell elongation and branching, and causes rounded clusters of murine inner medullary connecting duct epithelial cells to generate tubules in culture. Unlike HGF-stimulated morphogenesis, which is mediated by the Ras signaling pathway, these responses depend on activation of protein kinase C-α. Nickel et al. find that the two pathways can operate in parallel, since HGF enhances this morphological change even in the polycystin-overexpressing cell.

(See article on pages 533–540.)

Polycystin 1 and 2 mutations represent the most common cause of dominantly inherited polycystic kidney disease. However, humans and mice are also subject to recessive disorders in which the kidneys, and sometimes the liver, pancreas, or ovaries, are subject to cyst formation. In mice, the analysis of these mutations has led to interest in the role of apical cilia in the development of these tissues and in a seemingly unrelated matter, the genesis of a left-right axis during embryogenesis. Several ciliary proteins, including one of the dynein-class motor proteins and polaris, a protein found in the basal body and the ciliary axoneme, are affected by these mutations. Hou and colleagues have now found that the mouse cpk gene encodes another such ciliary protein, termed cystin, a putative scaffold protein that may bind directly to the axonemal membrane. Cystin, like polaris, localizes to the axoneme of kidney cell cilia and is presumed to have a similar distribution in biliary and other epithelial cells. Mutation of cpk leads to renal and biliary cysts but is not reported to disrupt left-right asymmetry in development. However, the body axis formation phenotype seen, for instance, in animals with defects in polaris appears to reflect a need for motile cilia, which direct a leftward flow of extracellular fluid across an embryonic structure called the “node”. In contrast, the cilia in the kidney and elsewhere are frequently nonmotile and may play other roles, perhaps in mechanosensory signaling. Whatever these roles, cystin would be predicted to be particularly needed in these structures, but perhaps not in the nodal cilia. Whether a cystin homolog is a candidate for human autosomal recessive polycystic kidney disease is still unknown, since no such sequence is identifiable in the current draft of the human genome sequence.