Nature Genetics pp 37 - 43 and p 10

Mutations in the gene BRCA1 account for approximately 50% of all inherited breast cancer cases. In such cases, affected patients have a defective copy of BRCA1 in all their cells and mutation of the remaining copy in mammary cells leads to breast cancer later in life. So far, studies of human breast cancer have been limited by the lack of a good animal model.

Chu-Xia Deng (of the National Institute of Diabetes, Digestive and Kidney Diseases) and colleagues now provide a 'conditional' mutant mouse that has one defective copy of Brca1 in all of its cells, with the second copy 'knocked out' specifically in mammary tissue. Tumours eventually develop in the mammary glands of these mice and their histopathology is strikingly similar to that of human tumours. The mutant mice also have smaller mammary glands compared with normal mice and their mammary ducts fail to completely penetrate the fat pad (although they are still able to nurse pups), indicating that Brca1 is needed for normal development of the mammary gland.

Deng and coworkers observed that, like human breast cancers with mutations in BRCA1, the tumours of the mutant mice frequently have mutations in the tumour-suppressor gene Trp53 (encoding p53). The researchers then demonstrated that introduction of a mutated copy of Trp53 into the Brca1-conditional mutant mice dramatically accelerated the rate of tumour formation. As discussed by Carina Dennis in an accompanying News & Views article, these findings suggest that loss of BRCA1 itself does not directly cause cancer, but rather 'destabilizes' the genome, resulting in mutation of other genes, including tumour suppressors. These mice provide a valuable model for identifying the molecular events arising from Brca1 deficiency, studying the environmental factors that influence the onset of tumour formation and assessing potential therapeutic strategies.

Nature Genetics pp 27 - 36 and pp 3 - 4

Similarities between rats and humans have made the rat a valuable model of human disease, particularly genetically 'complex' disease such as diabetes, hypertension and behavioural disorders. Genetic studies of the rat have, however, been limited by the lack of a high-resolution map to help geneticists navigate their way around the rat genome. This problem is now overcome by Akira Tanigami (of Otsuka GEN Research Institute), Michael James (of the Wellcome Trust Centre for Human Genetics) and colleagues, who have created the first high-resolution whole-genome map of the rat.

The researchers laid down the map's framework by first using a radiation hybrid panel - a series of cell lines each of which contains a fragment of a rat chromosome. The small amount of rat chromosomal material in each cell line allowed them to determine where genetic markers (a geneticist's 'signposts') are located on each chromosomal fragment and the position of each marker with respect to a neighbouring marker. This information was then used to piece together a map of the rat genome that consists of 5,255 genetic signposts. Tanigami, James and colleagues then went on to create a comparative map between genomes of the rat, human and another rodent popular with geneticists, the mouse. They found that large regions of the rat genome have a similar structure and arrangement of genes as that of human and mouse. Comparative maps are useful because they enable information about genomic organization from one species to be transferred to another and provide insight into genomic evolution.

These genome and comparative maps of the rat will greatly facilitate the identification of genes controlling traits and disease, as well as arming the research community with the resources needed to undertake the genome sequencing of the rat. As discussed by Joseph Nadeau (of Case Western Reserve University), in an accompanying News & Views article, these maps now firmly place the rat at the table with other key model organisms of the Genomic Revolution.

Nature Genetics pp 69 - 73

Cleft palate, which arises from incomplete fusion of the palatal shelves, is a common congenital birth defect, with an incidence of 1 in 1,000 live births among individuals of European descent. The defect is often inherited, but the large number of genes involved in facial development has confounded geneticists. Several reports have linked cleft palate with the gene TGFA, encoding the transforming growth factor-alpha (TGF-alpha). A report by Rik Derynck, Zena Werb (of University of California, San Francisco) and colleagues now reveals that the signalling pathway through which TGF-alpha acts is crucial for normal craniofacial development and provides insight into how alteration of TGFA can cause cleft palate. The researchers generated mice lacking the receptor for TGF-alpha, the epidermal growth factor receptor (Egfr), and found that these mice frequently had cleft palate, in addition to other facial abnormalities, including pointed snouts and shortened lower jaws.

Palate fusion is orchestrated by a series of events. The edges of the two developing palatal shelves are coated with a layer of epithelial cells, and are separated from each other by a basal membrane. Molecular signals from the basal membrane keep the epithelial cells growing and dividing. Fusion of the shelves depends on the basal membrane being digested away by enzymes called matrix metalloproteinases (MMPs). In the absence of signals from the basal membrane, the epithelial cells die, migrate or change their identity - this allows the palatal shelves to fuse. Egfr-deficient mice have decreased levels of MMPs, indicating that impaired Egfr signalling reduces MMP activity, leaving the basal membrane intact and inhibiting palate fusion.

These findings reveal how defects in Egfr signalling inhibit palate closure and raise the possibility that mutations of genes encoding additional binding partners of the Egfr receptor, as well as the downstream targets of the Egfr signalling pathway, may cause human cleft palate.