Neuropeptide Y functions as a neuroproliferative factor

Neuropeptide Y (NPY) has a number of functions in mammalian physiology. Here we identify a role for NPY in promoting proliferation of postnatal neuronal precursor cells. NPY is synthesized in the postnatal olfactory epithelium by sustentacular cells, previously proposed to function only in structural support. Mice with a targeted deletion of NPY contain half as many dividing olfactory neuronal precursor cells as do controls. Furthermore, NPY-deficient mice develop significantly fewer olfactory neurons by adulthood. NPY acts on multipotent neuronal precursor or basal cells to activate rapidly and transiently the extracellular signal-regulated kinase (ERK)1/2 subgroup of mitogen-activated protein kinases. The NPY Y1 receptor subtype appears to mediate this effect. The ability of NPY to induce neuronal precursor proliferation is mediated by protein kinase C (PKC), indicating an upstream PKC-dependent activation of ERK1/2. These results indicate that NPY may regulate neuronal precursor proliferation in the adult mammal.     

Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10

The stimulation of glucose uptake by insulin in muscle and adipose tissue requires translocation of the GLUT4 glucose transporter protein from intracellular storage sites to the cell surface. Although the cellular dynamics of GLUT4 vesicle trafficking are well described, the signalling pathways that link the insulin receptor to GLUT4 translocation remain poorly understood. Activation of phosphatidylinositol-3-OH kinase (PI(3)K) is required for this trafficking event, but it is not sufficient to produce GLUT4 translocation. We previously described a pathway involving the insulin-stimulated tyrosine phosphorylation of Cbl, which is recruited to the insulin receptor by the adapter protein CAP. On phosphorylation, Cbl is translocated to lipid rafts. Blocking this step completely inhibits the stimulation of GLUT4 translocation by insulin. Here we show that phosphorylated Cbl recruits the CrkII-C3G complex to lipid rafts, where C3G specifically activates the small GTP-binding protein TC10. This process is independent of PI(3)K, but requires the translocation of Cbl, Crk and C3G to the lipid raft. The activation of TC10 is essential for insulin-stimulated glucose uptake and GLUT4 translocation. The TC10 pathway functions in parallel with PI(3)K to stimulate fully GLUT4 translocation in response to insulin.     

Atomic-beam alignment of inorganic materials for liquid-crystal displays

The technique used to align liquid crystals-rubbing the surface of a substrate on which a liquid crystal is subsequently deposited-has been perfected by the multibillion-dollar liquid-crystal display industry. However, it is widely recognized that a non-contact alignment technique would be highly desirable for future generations of large, high-resolution liquid-crystal displays. A number of alternative alignment techniques have been reported, but none of these have so far been implemented in large-scale manufacturing. Here, we report a non-contact alignment process, which uses low-energy ion beams impinging at a glancing angle on amorphous inorganic films, such as diamond-like carbon. Using this approach, we have produced both laptop and desktop displays in pilot-line manufacturing, and found that displays of higher quality and reliability could be made at a lower cost than the rubbing technique. The mechanism of alignment is explained by adopting a random network model of atomic arrangement in the inorganic films. Order is induced by exposure to an ion beam because unfavourably oriented rings of atoms are selectively destroyed. The planes of the remaining rings are predominantly parallel to the direction of the ion beam.     

Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase

Response to genotoxic stress can be considered as a multistage process involving initiation of cell-cycle arrest and maintenance of arrest during DNA repair. Although maintenance of G2/M checkpoints is known to involve Chk1, Chk2/Rad53 and upstream components, the mechanisms involved in its initiation are less well defined. Here we report that p38 kinase has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. In vivo, inhibition of p38 prevents both phosphorylation of Cdc25B at serine 309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo Cdc25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation.     

The Ph1 locus is needed to ensure specific somatic and meiotic centromere association

The correct pairing and segregation of chromosomes during meiosis is essential for genetic stability and subsequent fertility. This is more difficult to achieve in polyploid species, such as wheat, because they possess more than one diploid set of similar chromosomes. In wheat, the Ph1 locus ensures correct homologue pairing and recombination. Although clustering of telomeres into a bouquet early in meiosis has been suggested to facilitate homologue pairing, centromeres associate in pairs in polyploid cereals early during floral development. We can now extend this observation to root development. Here we show that the Ph1 locus acts both meiotically and somatically by reducing non-homologous centromere associations. This has the effect of promoting true homologous association when centromeres are induced to associate. In fact, non-homologously associated centromeres separate at the beginning of meiosis in the presence, but not the absence, of Ph1. This permits the correction of homologue association during the telomere-bouquet stage in meiosis. We conclude that the Ph1 locus is not responsible for the induction of centromere association, but rather for its specificity.     

Phagocytosis and clearance of apoptotic cells is mediated by MER

Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. mer(kd) mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from mer(kd) mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in mer(kd) mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.     

Reproductive isolation caused by colour pattern mimicry

Speciation is facilitated if ecological adaptation directly causes assortative mating, but few natural examples are known. Here we show that a shift in colour pattern mimicry was crucial in the origin of two butterfly species. The sister species Heliconius melpomene and Heliconius cydno recently diverged to mimic different model taxa, and our experiments show that their mimetic coloration is also important in choosing mates. Assortative mating between the sister species means that hybridization is rare in nature, and the few hybrids that are produced are non-mimetic, poorly adapted intermediates. Thus, the mimetic shift has caused both pre-mating and post-mating isolation. In addition, individuals from a population of H. melpomene allopatric to H. cydno court and mate with H. cydno more readily than those from a sympatric population. This suggests that assortative mating has been enhanced in sympatry.     

Linkage disequilibrium in the human genome

With the availability of a dense genome-wide map of single nucleotide polymorphisms (SNPs), a central issue in human genetics is whether it is now possible to use linkage disequilibrium (LD) to map genes that cause disease. LD refers to correlations among neighbouring alleles, reflecting 'haplotypes' descended from single, ancestral chromosomes. The size of LD blocks has been the subject of considerable debate. Computer simulations and empirical data have suggested that LD extends only a few kilobases (kb) around common SNPs, whereas other data have suggested that it can extend much further, in some cases greater than 100 kb. It has been difficult to obtain a systematic picture of LD because past studies have been based on only a few (1-3) loci and different populations. Here, we report a large-scale experiment using a uniform protocol to examine 19 randomly selected genomic regions. LD in a United States population of north-European descent typically extends 60 kb from common alleles, implying that LD mapping is likely to be practical in this population. By contrast, LD in a Nigerian population extends markedly less far. The results illuminate human history, suggesting that LD in northern Europeans is shaped by a marked demographic event about 27,000-53,000 years ago.