The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

SummaryMutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis.PaperClip

Although kidneys of equal size can vary 10-fold in nephron number at birth, discovering what regulates such variation has been hampered by a lack of quantitative parameters defining kidney development. Here we report a comprehensive, quantitative, multiscale analysis of mammalian kidney development in which we measure changes in cell number, compartment volumes, and cellular dynamics across the entirety of organogenesis, focusing on two key nephrogenic progenitor populations: the ureteric epithelium and the cap mesenchyme. In doing so, we describe a discontinuous developmental program governed by dynamic changes in interactions between these key cellular populations occurring within a previously unappreciated structurally stereotypic organ architecture. We also illustrate the application of this approach to the detection of a subtle mutant phenotype. This baseline program of kidney morphogenesis provides a framework for assessing genetic and environmental developmental perturbation and will serve as a gold standard for the analysis of other organs.

Fraser syndrome is a rare recessive disorder characterized by cryptophthalmos, syndactyly, renal defects, and a range of other developmental abnormalities. Because of their extensive phenotypic overlap, the mouse blebbing mutants have been considered models of this disorder, and the recent isolation of mutations in Fras1 in both the blebbed mouse and human Fraser patients confirms this hypothesis. Here we report the identification of mutations in an extracellular matrix gene Fras1-related extracellular matrix gene 1 (Frem1) in both the classic head blebs mutant and in an N-ethyl-N-nitrosourea-induced allele. We show that inactivation of the gene results in the formation of in utero epidermal blisters beneath the lamina densa of the basement membrane and also in renal agenesis. Frem1 is expressed widely in the developing embryo in regions of epithelial͞mesenchymal interaction and epidermal remodeling. Furthermore, Frem1 appears to act as a dermal mediator of basement membrane adhesion, apparently independently of the other known ''blebs'' proteins Fras1 and Grip1. Unlike both Fras1 and Grip1 mutants, collagen VI and Fras1 deposition in the basement membrane is normal, indicating that the protein plays an independent role in epidermal differentiation and is required for epidermal adhesion during embryonic development. Human Fraser syndrome (OMIM no. 219000) is a rare recessive disorder characterized by cryptophthalmos, softtissue syndactyly, and a range of other developmental malformations, including renal agenesis, heart defects, reproductive tract anomalies, and deafness (1). Cryptophthalmos, in which skin covers the globe of the eye, is the most common malformation and is apparent in Ϸ90% of patients. Because of their similar phenotypes, the family of mouse blebbing mutants are considered models of Fraser syndrome (2-4). These mice are characterized by unilateral and bilateral cryptophthalmos, softtissue syndactyly, and a range of other defects encompassing abnormalities of the kidney, skin, hair, and CNS. The mutant family comprises four mapped and one umapped loci known as blebbed, eye blebs, head blebs (heb), myelencephalic blebs, and fetal hematoma (2).All of these mutants are characterized by the formation of epidermal blisters from Ϸ12 days postcoitum (dpc) and, as the embryo ages, these can become hemorrhagic. The epidermis of adult blebs mice is largely normal, suggesting that the genes mutated in these animals are uniquely required for maintaining epidermal adhesion only during embryonic development. Many defects observed in blebs mice, such as syndactyly and cryptophthalmos, are likely a consequence of epidermal delamination and subsequent disruption of epithelial͞mesenchymal interactions required for normal tissue differentiation, although such a mechanism is harder to invoke for defects such as renal agenesis (3). The formation of blisters on the head, limbs, and rump also suggests that the initial separation of the epidermis may be mediated by in utero friction.The recent identification of mutation...