Greg Barsh

Chimeric homeobox gene E2A-PBX1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice

Expression of the homeobox fusion gene E2A-PBX1 under control of the immunoglobulin heavy chain enhancer efficiently induced malignancies in transgenic mice. All animals died before 5 months of age with lymphomas that demonstrated phenotypes consistent with transitional intermediate thymocytes (CD4+/CD8+/CD3med). E2A-PBX1 also markedly altered lymphoid development in pretumorous animals, reducing the number of thymocytes and bone marrow B lineage progenitors to 20% of normal levels. In spite of the observed reductions in lymphoid cells, premalignant animals contained significantly increased numbers of cycling thymocytes, but a higher proportion was also undergoing apoptosis, suggesting that increased cell death resulted in the marked lymphopenias. These data indicate that the chimeric homeodomain protein E2A-PBX1 paradoxically induces both proliferation and apoptosis in lymphoid cells, suggesting an in vivo association between nuclear oncogene-induced cell cycle progression and programed cell death.

Microarray Profiling of Human Skeletal Muscle Reveals That Insulin Regulates ∼800 Genes during a Hyperinsulinemic Clamp

Insulin action in target tissues involved precise regulation of gene expression. To define the set of insulin-regulated genes in human skeletal muscle, we analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308 cDNA element microarrays, we found that the mRNA expression of 762 genes, including 353 expressed sequence tags, was significantly modified during insulin infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with known function are novel targets of insulin. They are involved in the transcriptional and translational regulation (29%), intermediary and energy metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle traffic (9%). Other categories consisted of genes coding for receptors, carriers, and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and elements of the immune response (5.5%). These results thus define a transcriptional signature of insulin action in human skeletal muscle. They will help to better define the mechanisms involved in the reduction of insulin effectiveness in pathologies such as type 2 diabetes mellitus, a disease characterized by defective regulation of gene expression in response to insulin.

Cloning and expression of the mouse homolog of the human α2-C2 adrenergic receptor

Summary Three subtypes of α2 adrenergic receptors have been identified in the human and rat. The subtype located on human chromosome 2 (α2-C2) is unique in that it is expressed mainly in the peripheral tissues and lacks sites for N-linked glycosylation. We isolated the gene encoding the mouse homolog of the human α2-C2 adrenergic receptor (Mα2-2H). The deduced amino acid sequence of the Mα2-2H shows 82% and 96% identity to the human α2-C2 and the rat RNGα2 adrenergic receptors, respectively. Southern blot analysis demonstrated that the Mα2-2H was encoded by a single copy gene and was distinct from the mouse homologs of the α2-C4 and α2-C10 adrenergic receptors. When expressed in COS-7 cells, the Mα2-2H exhibited a pharmacological profile similar to the human α2-C2 and rat RNGα2 receptors.

From Agouti to Pomc—100 years of fat blonde mice

Studies of mice deficient for proopiomelanocortin (Pomc) yield surprising results, and finally take us beyond the Ay model of melanocortin deficiency (pages 1066–1070).

How Hair Gets Its Pigment

Mutations in the transcription factor Foxn1 cause the nude phenotype in mice, which is characterized by a lack of visible hair. New work by Weiner et al. (2007) in this issue of Cell now shows that Foxn1 also contributes to hair color by marking which cells are to receive pigment from melanocytes.

Mahogany/Attractin: Enroute from Phenotype to Function

The mouse mahogany mutation affects melanocortin signaling pathways that regulate energy homeostasis and hair color. The gene mutated in mahogany mice encodes attractin, a large transmembrane protein that is broadly expressed and conserved among multicellular animals. Mouse attractin is likely to have additional roles outside melanocortin signaling, and cloning of the gene provides information that can be used to form testable hypotheses about its biochemical function.

Genitopatellar syndrome: Expanding the phenotype and excluding mutations in LMX1B and TBX4†

Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio‐ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail‐patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

Tabby pattern genetics - a whole new breed of cat.

Much of what we know about pigment cell biology comes from studying laboratory mice, yet the conservation of gene action and interaction across domesticated animals, including horses, cattle, pigs, and dogs, is firm evidence that most aspects of color variation are conserved in mammals. The domestic cat, however, is a special case in which variation within and among breeds exhibits a fascinating glimpse into an entirely new area of color variation as exemplified by tabby patterns. Periodic patterns with color markings spaced at non-random intervals are common in nature and evident in all major mammalian orders – stripes on chipmunks, reticulated markings on giraffes and hyenas, tail rings on lemurs, and, of course, tabby stripes on domestic cats. The similar nature but diverse manifestation among these patterns suggests they are formed by a conserved, adaptable, and largely unexplored mechanism. Periodic patterns are conspicuously missing from the laboratory mouse, but the cat stands out as a unique genetic model in which recent work from Eizirik et al. (2010) provides new genetic insight. Domestic cats have four distinct and heritable coat patterns – ticked, mackerel, blotched, and spotted – that are collectively referred to as tabby markings (Figure 1). These patterns are a composite of two features: (i) a light background component resulting from individual hairs with a subapical light-colored band and (ii) a superimposed darker component resulting from unbanded hairs. The ticked phenotype refers to the absence of any superimposed pattern, leaving only the banded or ‘ticked’ background color. Mackerel, blotched, and spotted phenotypes describe variations of the tabby pattern, in which the darker component forms either periodic vertical stripes (mackerel), whorls (blotched), or leopard-like spots (as in the Ocicat or Egyptian mau breeds of domestic cats). The periodicity of tabby markings distinguishes them in a fundamental way from other characteristic but randomly displayed markings, such as the tricolor patches on a calico cat or the black spots on a Dalmatian. These random patterns arise from events that are stochastically initiated (like inactivation of an X chromosome in females or survival of a melanocyte cluster) but stably maintained, either through epigenetic mechanisms as with X inactivation, or a developmental process, as with a limited window for neural crest migration. By contrast, periodic patterns must arise from a mechanism that is specifically programed to be spatially constrained. What are the molecules and cells that underlie tabby patterns? A genetic approach to this question began nearly a century ago when Phineas Whiting described three tabby ‘banding factors’, noting a simple pattern of inheritance for each: ticked is dominantly inherited relative to mackerel and blotched, whereas blotched is recessively inherited relative to ticked or to mackerel (Whiting, 1918). Whiting posited a single locus (T ) with three alleles – ticked (T ), mackerel (T ), and blotched (t ). That view has now been revised by the recent work of Eizirik et al. (2010), who applied a genome-wide panel of molecular markers to pedigrees segregating the different coat color patterns, and thereby discovered that two loci were involved in determining the difference between ticked, mackerel, and blotched patterns (Figure 1). In this modern view of cat pattern genetics, the Tabby locus determines the type of pattern, with the Ta (Mackerel) allele dominant to the Ta (Blotched ) allele, while a second locus, now known as Ticked, determines the absence or presence of pattern, with the Ti A allele dominant to the Ti allele. The nomenclature has become complicated; similar to Eizirik et al. (2010), we use lower case roman to describe the

337 GENITOPATELLAR SYNDROME: EXPANDING THE PHENOTYPE

Genitopatellar syndrome is a rare condition characterized by absent patellae, hydronephrosis, and scrotal hypoplasia in males Clitoral hypertrophy and hypoplastic labia have been described in the two reported female patients. We describe the thirteenth case of genitopatellar syndrome in a female, who also has bilateral radioulnar synostosis and colpocephaly. Our patient was ascertained prenatally when an ultrasound revealed severe bilateral hydronephrosis and an atrial septal defect. After delivery, microcephaly, mild camptodactyly, unusual knee dimples, lower extremity contractures, and unilateral clubfoot were noted. MRI and ultrasound of the knees confirmed absent patellae. The genitalia showed clitoral hypertrophy with hypoplastic labia. Further radiologic evaluation demonstrated bilateral radioulnar synostosis, cervical ribs, hypoplastic iliac bones, and splayed pubic bones. MRI revealed agenesis of the corpus callosum with colpocephaly. Only twelve cases of the genitopatellar syndrome have been published in the literature to our knowledge. Additional reported findings include microcephaly, lower extremity contractures, clubfeet, congenital heart defects, and agenesis of the corpus callosum. Although a number of conditions exist with absent or hypoplastic patellae, the constellation of findings in these patients is unique and not explained by other syndromes or associations. The findings in our case are identical to earlier cases, with the exception that radioulnar synostosis and colpocephaly have not previously been reported. The association of absent patellae with radioulnar synostosis and other skeletal anomalies suggests that a generalized bone dysplasia may be an underlying component of genitopatellar syndrome. Karyotype and metabolic tests have not revealed an underlying etiology in any patient identified to date. The prognosis for affected individuals is poor as most do not survive infancy. Although a few children have survived the first decade, they remain non-ambulatory and nonverbal with severe mental retardation. The presence of colpocephaly in our patient also suggests a similarly poor prognosis.