Mutations in a new member of the chromodomain gene family cause CHARGE syndrome

CHARGE syndrome is a common cause of congenital anomalies affecting several tissues in a nonrandom fashion. We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.     

Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus

Kaposi sarcoma is considered a neoplasm of lymphatic endothelium infected with Kaposi sarcoma-associated herpesvirus. It is characterized by the expression of lymphatic lineage-specific genes by Kaposi sarcoma tumor cells. Here we show that infection of differentiated blood vascular endothelial cells with Kaposi sarcoma-associated herpesvirus leads to their lymphatic reprogramming; induction of approximately 70% of the main lymphatic lineage-specific genes, including PROX1, a master regulator of lymphatic development; and downregulation of blood vascular genes.     

A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling

PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) alphaalpha and alphabeta dimers. Here we show that Pdgfc(-/-) mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra(-/-) embryos. Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated.     

Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.     

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.     

The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.     

Articulated Palaeozoic fossil with 17 plates greatly expands disparity of early chitons

Modern chitons (Mollusca: Polyplacophora) possess a highly conserved skeleton of eight shell plates (valves) surrounded by spicules or scales, and fossil evidence suggests that the chiton skeleton has changed little since the first appearance of the class in the Late Cambrian period (about 500 million years before present, Myr bp). However, the Palaeozoic problematic taxon Multiplacophora, in spite of having a more complex skeleton, shares several derived characters with chitons. The enigmatic status of the Multiplacophora is due in part to the fact that its members had an exoskeleton of numerous calcium carbonate valves that usually separated after death. A new articulated specimen from the Carboniferous period (about 335 Myr bp) of Indiana reveals that multiplacophorans had a dorsal protective surface composed of head and tail valves, left and right columns of overlapping valves (five on each side), and a central zone of five smaller valves, all surrounded by an annulus of large spines. Here we describe and name the articulated specimen and present evidence that multiplacophorans were chitons. Thus the highly conserved body plan of living chitons belies the broad disparity of this clade during the Palaeozoic era.     

Regional climate shifts caused by gradual global cooling in the Pliocene epoch

The Earth's climate has undergone a global transition over the past four million years, from warm conditions with global surface temperatures about 3 degrees C warmer than today, smaller ice sheets and higher sea levels to the current cooler conditions. Tectonic changes and their influence on ocean heat transport have been suggested as forcing factors for that transition, including the onset of significant Northern Hemisphere glaciation approximately 2.75 million years ago, but the ultimate causes for the climatic changes are still under debate. Here we compare climate records from high latitudes, subtropical regions and the tropics, indicating that the onset of large glacial/interglacial cycles did not coincide with a specific climate reorganization event at lower latitudes. The regional differences in the timing of cooling imply that global cooling was a gradual process, rather than the response to a single threshold or episodic event as previously suggested. We also find that high-latitude climate sensitivity to variations in solar heating increased gradually, culminating after cool tropical and subtropical upwelling conditions were established two million years ago. Our results suggest that mean low-latitude climate conditions can significantly influence global climate feedbacks.