Structure,biosynthesis and functions of glycoprotein glycans

Since the pioneering work on structure and function of heteroglycans compiled in the classical books edited by A. Gottschalk in 1972¹, there have been several promising developments in glycoconjugate research, as reviewed in this article.In Part 1, contributed by A. Kobata, current knowledge on heteroglycan structures is presented and representative examples taken from higher organisms are given. Part 2, written by J. F. G. Vliegenthart and J. P. Kamerling, covers the most important achievements in methodology: procedures to obtain pure glycans and to analyze their structures. Part 3, contributed by J. Paulson, is devoted to biosynthesis of glycans now describable as pathways since several of the glycosyltransferases have been isolated and analyzed for specificity. In Part 4, contributed by E. Buddecke, current knowledge on functional roles of glycans is presented. It will become apparent that the prerequisite for valid work either in biosynthetic or functional context depends on solid structural information. This is particularly true whenever glycosyltransferase reaction products are being analyzed, or glycans involved in biological functions are investigated. Although in past years, a great deal of important knowledge has been gathered by use of crude glycosidase or glycosyltransferase activities (a notable example is found in reference 2), one may now postulate that glycans implicated in biological reactions should be thoroughly analyzed.This review may familiarize newcomers with the field of glycoconjugate research with special emphasis on glycoprotein glycans. Glycolipids are not included in this article as they have recently been reviewed by S. I. Hakomori³. The reader is also referred to several excellent monographs^4,5 and the Proceedings of the Glycoconjugate Symposia held biannually^6–8.     

Corridors of migrating neurons in the human brain and their decline during infancy

The subventricular zone of many adult non-human mammals generates large numbers of new neurons destined for the olfactory bulb. Along the walls of the lateral ventricles, immature neuronal progeny migrate in tangentially oriented chains that coalesce into a rostral migratory stream (RMS) connecting the subventricular zone to the olfactory bulb. The adult human subventricular zone, in contrast, contains a hypocellular gap layer separating the ependymal lining from a periventricular ribbon of astrocytes. Some of these subventricular zone astrocytes can function as neural stem cells in vitro, but their function in vivo remains controversial. An initial report found few subventricular zone proliferating cells and rare migrating immature neurons in the RMS of adult humans. In contrast, a subsequent study indicated robust proliferation and migration in the human subventricular zone and RMS. Here we find that the infant human subventricular zone and RMS contain an extensive corridor of migrating immature neurons before 18 months of age but, contrary to previous reports, this germinal activity subsides in older children and is nearly extinct by adulthood. Surprisingly, during this limited window of neurogenesis, not all new neurons in the human subventricular zone are destined for the olfactory bulb--we describe a major migratory pathway that targets the prefrontal cortex in humans. Together, these findings reveal robust streams of tangentially migrating immature neurons in human early postnatal subventricular zone and cortex. These pathways represent potential targets of neurological injuries affecting neonates.     

Genetic mapping with SNP markers in Drosophila.

Map-based positional cloning of Drosophila melanogaster genes is hampered by both the time-consuming, error-prone nature of traditional methods for genetic mapping and the difficulties in aligning the genetic and cytological maps with the genome sequence. The identification of sequence polymorphisms in the Drosophila genome will make it possible to map mutations directly to the genome sequence with high accuracy and resolution. Here we report the identification of 7,223 single-nucleotide polymorphisms (SNPs) and 1,392 insertions/deletions (InDels) in common laboratory strains of Drosophila. These sequence polymorphisms define a map of 787 autosomal marker loci with a resolution of 114 kb. We have established PCR product-length polymorphism (PLP) or restriction fragment-length polymorphism (RFLP) assays for 215 of these markers. We demonstrate the use of this map by delimiting two mutations to intervals of 169 kb and 307 kb, respectively. Using a local high-density SNP map, we also mapped a third mutation to a resolution of approximately 2 kb, sufficient to localize the mutation within a single gene. These methods should accelerate the rate of positional cloning in Drosophila.     

Winter habitats and foods of Blue Grouse in the Sheeprock Mountains, Utah

Winter habitat use and food habits of Blue Grouse ( Dendragapus obscurus ) were studied in an isolated Utah desert mountain range that contained little typical Douglas-fir ( Pseudotsuga menziesii ) winter habitat. Habitat use was concentrated in the Douglas-fir and pinyon ( Pinus edulis )-juniper ( Juniperus spp. ) habitat. Douglas-fir and pinyon pine were the most consumed foods. Other foods that represented >15% of the composition of an individual fecal sample were limber pine ( Pinus flexilis ), mahogany ( Cercocarpus ledifoliu ), juniper, and an Anteunaria-Cirsium type. The breadth in winter diet indicates that Blue Grouse may successfully occupy other habitats when typical winter habitat is scarce.     

Vaults and the major vault protein: Novel roles in signal pathway regulation and immunity

The unique and evolutionary highly conserved major vault protein (MVP) is the main component of ubiquitous, large cellular ribonucleoparticles termed vaults. The 100 kDa MVP represents more than 70% of the vault mass which contains two additional proteins, the vault poly (ADP-ribose) polymerase (vPARP) and the telomerase-associated protein 1 (TEP1), as well as several short untranslated RNAs (vRNA). Vaults are almost ubiquitously expressed and, besides chemotherapy resistance, have been implicated in the regulation of several cellular processes including transport mechanisms, signal transmissions and immune responses. Despite a growing amount of data from diverse species and systems, the definition of precise vault functions is still highly complex and challenging. Here we review the current knowledge on MVP and vaults with focus on regulatory functions in intracellular signal transduction and immune defence. Received 27 June 2008; received after revision 25 July 2008; accepted 30 July 2008     

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.     

Isolation of a candidate gene for Norrie disease by positional cloning.

The gene for Norrie disease, an X-linked disorder characterized by progressive atrophy of the eyes, mental disturbances and deafness, has been mapped to chromosome Xp11.4 close to DXS7 and the monoamine oxidase (MAO) genes. By subcloning a YAC with a 640 kilobases (kb) insert which spans the DXS7-MAOB interval we have generated a cosmid contig which extends 250 kb beyond the MAOB gene. With one of these cosmids, microdeletions were detected in several patients with Norrie disease. Screening of cDNA libraries has enabled us to isolate and sequence a likely candidate gene for Norrie disease which is expressed in retina, choroid and fetal brain. No homologous sequences were found in DNA and protein databases indicating that this cDNA is part of a gene encoding a 'pioneer' protein.     

Early optical emission from the gamma-ray burst of 4 October 2002

Observations of the long-lived emission--or 'afterglow'--of long-duration gamma-ray bursts place them at cosmological distances, but the origin of these energetic explosions remains a mystery. Observations of optical emission contemporaneous with the burst of gamma-rays should provide insight into the details of the explosion, as well as into the structure of the surrounding environment. One bright optical flash was detected during a burst, but other efforts have produced negative results. Here we report the discovery of the optical counterpart of GRB021004 only 193 seconds after the event. The initial decline is unexpectedly slow and requires varying energy content in the gamma-ray burst blastwave over the course of the first hour. Further analysis of the X-ray and optical afterglow suggests additional energy variations over the first few days.