Kelly A. McGowan

Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects

Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin (Dsk) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.

Laminins and human disease

The laminin protein family has diverse tissue expression patterns and is involved in the pathology of a number of organs, including skin, muscle, and nerve. In the skin, laminins 5 and 6 contribute to dermal‐epidermal cohesion, and mutations in the constituent chains result in the blistering phenotype observed in patients with junctional epidermolysis bullosa (JEB). Allelic heterogeneity is observed in patients with JEB: mutations that results in premature stop codons produce a more severe phenotype than do missense mutations. Gene therapy approaches are currently being studied in the treatment of this disease. A blistering phenotype is also observed in patients with acquired cicatricial pemphigoid (CP). Autoantibodies targeted against laminins 5 and 6 destabilize epithelial adhesion and are pathogenic. In muscle cells, laminin α2 is a component of the bridge that links the actin cytoskeleton to the extracellular matrix. In patients with laminin α2 mutations, the bridge is disrupted and mature muscle cells apoptose. Congenital muscular dystrophy (CMD) results. The role of laminin in diseases of the nervous system is less well defined, but the extracellular protein has been shown to serve an important role in peripheral nerve regeneration. The adhesive molecule influences neurite outgrowth, neural differentiation, and synapse formation. The broad spatial distribution of laminin gene products suggests that laminin may be involved in a number of diseases for which pathogenic mechanisms are still being unraveled. Microsc. Res. Tech. 51:262–279, 2000.

Specifying and sustaining pigmentation patterns in domestic and wild cats

What Kitty Shares with Kings Although long-studied, the underlying basis of mammalian coat patterns remains unclear. By studying a large number of cat species and varieties, Kaelin et al. (p. 1536) identified two genes, Taqpep and Edn3, as critical factors in the development of feline pigment patterns. Mutations in Taqpep are responsible for the blotched tabby pattern in domestic cats and the unusual coat of wild king cheetahs. Gene expression patterns in cat and cheetah skin suggest that Edn3 is a likely regulator of felid hair color. The findings support a common model for coat and pigment pattern formation in domestic and wild cats. The genes specifying tabby cat coat patterns also affect big cats, including king cheetahs. Color markings among felid species display both a remarkable diversity and a common underlying periodicity. A similar range of patterns in domestic cats suggests a conserved mechanism whose appearance can be altered by selection. We identified the gene responsible for tabby pattern variation in domestic cats as Transmembrane aminopeptidase Q (Taqpep), which encodes a membrane-bound metalloprotease. Analyzing 31 other felid species, we identified Taqpep as the cause of the rare king cheetah phenotype, in which spots coalesce into blotches and stripes. Histologic, genomic expression, and transgenic mouse studies indicate that paracrine expression of Endothelin3 (Edn3) coordinates localized color differences. We propose a two-stage model in which Taqpep helps to establish a periodic pre-pattern during skin development that is later implemented by differential expression of Edn3.

Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome

Reduced gene dosage of ribosomal protein subunits has been implicated in 5q- myelodysplastic syndrome and Diamond Blackfan anemia, but the cellular and pathophysiologic defects associated with these conditions are enigmatic. Using conditional inactivation of the ribosomal protein S6 gene in laboratory mice, we found that reduced ribosomal protein gene dosage recapitulates cardinal features of the 5q- syndrome, including macrocytic anemia, erythroid hypoplasia, and megakaryocytic dysplasia with thrombocytosis, and that p53 plays a critical role in manifestation of these phenotypes. The blood cell abnormalities are accompanied by a reduction in the number of HSCs, a specific defect in late erythrocyte development, and suggest a disease-specific ontogenetic pathway for megakaryocyte development. Further studies of highly purified HSCs from healthy patients and from those with myelodysplastic syndrome link reduced expression of ribosomal protein genes to decreased RBC maturation and suggest an underlying and common pathophysiologic pathway for additional subtypes of myelodysplastic syndrome.

Animal models of Diamond Blackfan anemia.

Diamond Blackfan anemia (DBA) is a genetic syndrome characterized by red blood cell aplasia in association with developmental abnormalities such as growth retardation, orofacial, hand or limb malformations, urogenital anomalies, and heart defects. The only known cause is heterozygosity for mutations in genes encoding ribosomal proteins. Understanding how defective ribosome biogenesis and function, important for all cells, causes defects in erythropoiesis and tissue-specific phenotypes during development is paramount to the evolution of effective treatment protocols. Here, we discuss how animal models based on mammals, insects, and fish replicate genetic or developmental aspects of DBA and have led to the identification of pathways and candidate molecules that are important in the pathogenesis of the disease. A recurring theme in many of these models suggests that defective ribosome biogenesis induces a p53-dependent cell cycle checkpoint in cells that require high levels of ribosome production and leads to cell type-specific, whole animal phenotypes.

Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses

Dun is a wild-type coat color in horses characterized by pigment dilution with a striking pattern of dark areas termed primitive markings. Here we show that pigment dilution in Dun horses is due to radially asymmetric deposition of pigment in the growing hair caused by localized expression of the T-box 3 (TBX3) transcription factor in hair follicles, which in turn determines the distribution of hair follicle melanocytes. Most domestic horses are non-dun, a more intensely pigmented phenotype caused by regulatory mutations impairing TBX3 expression in the hair follicle, resulting in a more circumferential distribution of melanocytes and pigment granules in individual hairs. We identified two different alleles (non-dun1 and non-dun2) causing non-dun color. non-dun2 is a recently derived allele, whereas the Dun and non-dun1 alleles are found in ancient horse DNA, demonstrating that this polymorphism predates horse domestication. These findings uncover a new developmental role for T-box genes and new aspects of hair follicle biology and pigmentation.

How the zebrafish got its stripes

Live-cell imaging and genetic tools reveal a new way in which pigment cells communicate in zebrafish