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PubMed2003

The usefulness of different density SNP maps for disease association studies of common variants.

Large-scale discovery and validation of single-nucleotide polymorphisms (SNPs) facilitates indirect association mapping. It has recently been estimated that, in Europeans, 77% of all SNPs with frequency of 10% or more could be ascertained through linkage disequilibrium (LD) by genotyping variants in the database dbSNP. Using a sampling approach from 73 genes with near complete SNP maps, we show here the usefulness of SNP maps at different densities and the large variability of SNP coverage in different genomic regions. While even sparse SNP maps are of some value to genetic mapping, in order to undertake disease association studies providing at least 80% of SNPs in 90% of genes, much denser maps need to be constructed, at more than one SNP per kb in some regions.

Chromosome Mapping↗
PubMed2001

NMDA-induced phosphorylation of the microtubule-associated protein MAP-2 is mediated by activation of nitric oxide synthase and MAP kinase.

Microtubule-associated protein MAP-2 is a neuronal phosphoprotein which modulates microtubule stability and spatial organization of signal transduction pathways. The functions of MAP-2 are modulated by phosphorylation. We studied the modulation of MAP-2 phosphorylation using the N-methyl- D-aspartate (NMDA) type of glutamate receptors and the signal transduction pathways mediating this modulation in primary cultures of rat cerebellar neurons. NMDA induced a rapid increase (330% of basal at 5 min) in MAP-2 phosphorylation which was not prevented by KN-62, indicating that it is not mediated by activation of Ca-calmodulin-dependent protein kinase. NMDA-induced phosphorylation of MAP-2 was inhibited by the nitric oxide synthase inhibitors nitroarginine and 7-nitroindazole and by PD098059 (an inhibitor of MAP kinase kinase), but was only slightly reduced by calphostin C or U-73122, inhibitors of protein kinase C and of phospholipase C, respectively. This indicates that the main pathway mediating NMDA-induced phosphorylation of MAP-2 is activation of nitric oxide synthase and subsequent activation of MAP kinase. We show that activation of NMDA receptors induces an activation of MAP kinase which is prevented by nitroarginine. The nitric oxide-generating agent (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) also induced activation of MAP kinase and increased phosphorylation of MAP-2. Other nitric oxide-generating agents (NOC-18 and NOR-3) also increased MAP-2 phosphorylation. The interplay between NMDA receptors-associated signal transduction pathways and MAP-2 may be involved in the modulation of neuronal responses to extracellular signals and in the regulation of neuronal function.

Animals↗
PubMed1996

The pool of map kinase associated with microtubules is small but constitutively active.

Mitogen-activated protein kinase (MAPK) is activated by many kinds of stimuli and plays an important role in integrating signal transduction cascades. MAPK is present abundantly in brain, where we have studied its association with microtubules. Immunofluorescence of primary hippocampal neurons revealed that MAPK staining co-localized with microtubules and biochemical analyses showed that MAPK co-purified with microtubules. Approximately 4% of MAPK in cytosolic extracts was associated with microtubules, where it was associated with both tubulin and microtubule-associated proteins (MAPs) fractions. Further fractionation of MAPs suggested that a portion of MAPK is associated with MAP2. An association with MAP2 was also demonstrated by co-immunoprecipitation and in vitro binding experiments. A similar association was shown for the juvenile MAP2 isoform, MAP2C. The pool of MAPK associated with microtubules had a higher activity relative to the nonassociated pool in both brain and proliferating PC12 cells. Although MAPK was activated by nerve growth factor in PC12 cells, the activity of microtubule-associated MAPK did not further increase. These results raise the possibility that microtubule-associated MAPK operates through constitutive phosphorylation activity to regulate microtubule function in neurons.

Animals↗
PubMed1986

Identification of a 34-kD polypeptide as a light chain of microtubule-associated protein-1 (MAP-1) and its association with a MAP-1 peptide that binds to microtubules.

We examined the association of a 34-kD light chain component to the heavy chains of MAP-1 using a monoclonal antibody that specifically binds the 34-kD component and labels neuronal microtubules in a specific and saturable manner. Immunoprecipitation of MAP-1 heavy chains together with the 34-kD component by the antibody indicates that the 34-kD polypeptide forms a complex with MAP-1 heavy chains. Both major isoforms of MAP-1 heavy chains (MAP-1A and MAP-1B) were found in the immunoprecipitate. Digestion of MAP-1 with alpha-chymotrypsin and analysis of the chymotryptic peptides reveals a 120-kD fragment of the MAP-1 heavy chain that binds to microtubules and is precipitable with the 34-kD light chain antibody, suggesting that the 34-kD light chain also binds to this domain of the molecule. Since microtubules that contain the 120-kD fragment lack the long lateral projections characteristic of microtubules with intact MAP-1, the 34-kD light chains may be localized at or near the microtubule surface.

Animals↗
PubMed2004

Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps.

Genetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences.

Alleles↗
PubMed1999

[Association of MAP kinases with the endoplasmic reticulum in NIH3T3 (HER14) and A431 cells].

Intracellular distribution of p42/p44 MAP-kinases in HER14 and A431 cell lines was investigated. Using subcellular fractionation and immunofluorescence approaches we have shown that in quiescent cells of both types MAP-kinases are associated with endoplasmic reticulum. Moreover, ER-localized MAP-kinases were shown to exist only in a nonphosphorylated form. In HER14 cells the epidermal growth factor (EGF) elevates the level of the ER-associated MAP-kinases. In contrast, exposure of A431 cells to EGF leads to a significant decrease in the observed association. The physiological role of this association is discussed.

3T3 Cells↗
PubMed1994

Microtubule-stabilizing activity of microtubule-associated proteins (MAPs) is due to increase in frequency of rescue in dynamic instability: shortening length decreases with binding of MAPs onto microtubules.

The role of microtubule associated proteins (MAPs) on the dynamic instability of microtubules was examined under a dark-field microscope using bovine brain tubulin purified by DEAE-Sepharose column chromatography. In the absence of MAPs, the transition from the shortening phase to the growing phase (the rescue) occurred rarely both in self-assembled microtubules and seeded ones, especially at the plus end. Even under the conditions unfavorable to stabilize microtubule, the addition of a small amount of crude MAPs or purified microtubule associated protein 2 (MAPs) to the microtubules allowed them to undergo the rescue. At increased concentrations of MAPs or MAP2, both the length change required for a rescue during shortening phase ("shortening length") and for a catastrophe (transition from the growing to the shortening phase) ("growth length") decreased. Under these conditions, the rescue often occurred at the same site where previous rescues occurred. Distribution of immunofluorescent MAP2 antibodies along individual microtubules showed that MAP2 molecules bound onto microtubules by forming discrete clusters. The number of MAP2 molecules per cluster was estimated to be between 25 and 60. Because both the "shortening length" and the distance between MAP2 clusters in a microtubule decreased with increased MAPs concentration, we suggest that the MAP2 clusters may form the specific site at which the shortening of the microtubule readily stops. MAP2 possibly regulates the dynamic instability by stopping the shortening, which is a prerequisite for the rescue.

Animals↗
PubMed1984

Interaction between rat brain microtubule associated proteins (MAPs) and free ribosomes from Xenopus oocyte: a possible mechanism for the in ovo distribution of MAPs.

The binding of microtubule associated proteins (MAPs) to free 80 S ribosomes isolated from Xenopus laevis oocytes inhibits in vitro tubulin assembly (Jessus et al., 1984). The inhibition of tubulin polymerisation was shown to be dependent upon GTP. The dose of GTP needed to induce 50% of the maximal effect was 0.5 mM. Furthermore, the inhibition is enhanced by pretreatment of the ribosomes with ATP-gamma-S, and partially abolished after phosphatase treatment, which strongly suggests that protein phosphorylation regulated the inhibitory effect. When fluorescent purified MAPs are microinjected into Xenopus laevis oocyte, they cap 1 h later the basal nuclear envelope; in contrast, when the fluorescent MAPs-ribosome complex is injected, the fluorescent MAPs remain in the cytoplasm and never reach the region underlying the nuclear envelope.

Animals↗
PubMed1990

Synthesis, axonal transport, and turnover of the high molecular weight microtubule-associated protein MAP 1A in mouse retinal ganglion cells: tubulin and MAP 1A display distinct transport kinetics.

Microtubule-associated proteins (MAPs) in neurons establish functional associations with microtubules, sometimes at considerable distances from their site of synthesis. In this study we identified MAP 1A in mouse retinal ganglion cells and characterized for the first time its in vivo dynamics in relation to axonally transported tubulin. A soluble 340-kD polypeptide was strongly radiolabeled in ganglion cells after intravitreal injection of [35S]methionine or [3H]proline. This polypeptide was identified as MAP 1A on the basis of its co-migration on SDS gels with MAP 1A from brain microtubules; its co-assembly with microtubules in the presence of taxol or during cycles of assembly-disassembly; and its cross-reaction with well-characterized antibodies against MAP 1A in immunoblotting and immunoprecipitation assays. Glial cells of the optic nerve synthesized considerably less MAP 1A than neurons. The axoplasmic transport of MAP 1A differed from that of tubulin. Using two separate methods, we observed that MAP 1A advanced along optic axons at a rate of 1.0-1.2 mm/d, a rate typical of the Group IV (SCb) phase of transport, while tubulin moved 0.1-0.2 mm/d, a group V (SCa) transport rate. At least 13% of the newly synthesized MAP 1A entering optic axons was incorporated uniformly along axons into stationary axonal structures. The half-residence time of stationary MAP 1A in axons (55-60 d) was 4.6 times longer than that of MAP 1A moving in Group IV, indicating that at least 44% of the total MAP 1A in axons is stationary. These results demonstrate that cytoskeletal proteins that become functionally associated with each other in axons may be delivered to these sites at different transport rates. Stable associations between axonal constituents moving at different velocities could develop when these elements leave the transport vector and incorporate into the stationary cytoskeleton.

Animals↗
PubMed1982

A taxol-dependent procedure for the isolation of microtubules and microtubule-associated proteins (MAPs).

The effect of the antimitotic drug taxol on the association of MAPs (microtubule-associated proteins) with microtubules was investigated. Extensive microtubule assembly occurred in the presence of Taxol at 37 degrees C. at 0 degrees C, and at 37 degrees C in the presence of 0.35 M NaCl, overcoming the inhibition of assembly normally observed under the latter two conditions. At 37 degrees C and at 0 degrees C, complete assembly of both tubulin and the MAPs was observed in the presence of Taxol. However, at elevated ionic strength, only tubulin assembled, forming microtubules devoid of MAPs. The MAPs could also be released from the surface of preformed microtubules by exposure to elevated ionic strength. These properties provided the basis for a rapid new procedure for isolating microtubules and MAPs of high purity from small amounts of biological material. The MAPs could be recovered by exposure of the microtubules to elevated ionic strength and subjected to further analysis. Microtubules and MAPs were prepared from bovine cerebral cortex (gray matter) and from HeLa cells. MAP 1, MAP2, and the tau MAPs, as well as species of Mr = 28,000 and 30,000 (LMW, or low molecular weight, MAPs) and a species of Mr = 70,000 were isolated from gray matter. Species identified as the 210,000 and 125,000 mol wt HeLa MAPs were isolated from HeLa cells. Microtubules were also prepared for the first time from white matter. All of the MAPs identified in gray matter preparations were identified in white matter, but the amounts of individual MAP species differed. The most striking difference in the two preparations was a fivefold lower level of MAP 2 relative to tubulin in white matter than in gray. The high molecular weigh MAP, MAP1, was present in equal ratio to tubulin in white and gray matter. These results indicate that MAP 1 and MAP2, as well as other MAP species, may have a different cellular or subcellular distribution.

Alkaloids↗
PubMed1981

Phosphorylation of microtubule-associated proteins (MAPs) and pH of the medium control interaction between MAPs and actin filaments.

Interaction of microtubule-associated proteins (MAPs) with actin filaments at neutral pH is inhibited by phosphorylation of MAPs. Phosphorylated MAPs are less potent than unphosphorylated ones in increasing the low-shear viscosity of actin filaments in the neutral pH range. The ability of unphosphorylated MAPs to crosslink actin filaments falls off sharply above pH 7.5. Upon phosphorylation, the crosslinking ability of the MAPs peaks sharply between pH 6.2 and 6.3. Thus, the MAPs-actin interaction can be regulated by phosphorylation of MAPs and small changes in the physiological range of pH.

Actins↗
PubMed1993

Distribution of microtubule-associated proteins (MAPs) in adult and embryonic mouse retinal explants: presence of the embryonic map, MAP5/1B, in regenerating adult retinal axons.

Microtubule-associated proteins (MAPs) are developmentally regulated proteins involved in microtubule polymerization and stabilization. We have asked whether MAPs in regenerating adult mouse retinal ganglion cell axons recapitulate the pattern of MAPs seen during development. Adult and Embryonic Day 15 (E15) mouse retinal segments were explanted onto laminin-coated coverslips and allowed to extend neurites in serum-free medium. Using a variety of monoclonal antibodies (Mabs), we stained adult and E15 explant cultures for early (MAP5) and late (MAP1, MAP2, MAP2a+b, tau) MAPs. Optic neurites growing from E15 explants were strongly immunoreactive for MAP5. Labeling was absent for MAP1 and MAP2a+b. Mabs to MAP2 and tau lightly stained axons and cell bodies, probably due to MAP2c and juvenile tau which are found in developing neurons. In adult explant cultures, both perikarya and axons were immunoreactive for MAP1. MAP2 and MAP2a+b labeled perikarya and fibers within the explant, and tau stained axons on the substrate. MAP5 immunoreactivity was intense in the adult explant cultures, labeling axons extending over the substrate and perikarya and dendrites in the explant in a pattern similar to that seen in E15 explants. In summary, adult retinal explants maintain their adult complement of MAPs, in showing high levels of MAP1, tau immunoreactivity restricted to neurites on the substrate, and MAP2 segregated into neurites and perikarya within the explant. The exception is MAP5 for which the pattern of immunoreactivity is similar in adult and E15 retinal explants.

Animals↗
PubMed1984

Polymorphism of tubulin oligomers in the presence of microtubule-associated proteins. Implications in microtubule assembly.

The interaction between tubulin and microtubule-associated proteins (MAPs) in solutions of cycled microtubule protein has been studied by using radioactively labeled MAPs. Kinetic data of MAP association to microtubules in the polymerization process indicate that an oligomer P of tubulin and MAPs is the polymerizing species. Analysis of MAP binding to microtubules formed from solutions in which the ratio MAPs/tubulin was varied shows evidence for a polymorphism of tubulin-MAP oligomers. When the ratio MAPs/tubulin is decreased by addition of dimeric tubulin to 3 times cycled microtubule protein, an oligomer P' less rich in MAPs than P and unable to incorporate in microtubules is formed. The data further show that while tau, MAP1, and MAP2 can bind to oligomer P, only MAP1 and MAP2 can bind to oligomer P'. Therefore, the interactions of tau factor and of MAP1 and MAP2 with tubulin follow different patterns.

Animals↗
PubMed1988

Rapid phosphorylation of microtubule-associated proteins through distinct mitogenic pathways.

Mitogenic stimulation of sparse quiescent Swiss 3T3 cells with serum induces a transient reorganization of microtubules which may be necessary for generation or transduction of the mitogenic signal(s). Recently, several studies have shown that microtubule-associated proteins (MAPs) modulate microtubule-mediated functions in vitro and in vivo. We have analyzed, by two-dimensional electrophoresis, the molecular changes in MAPs associated with microtubules in situ following cell activation. By as early as 15 min after addition of serum, several of the MAPs present in quiescent cells are lost from the assembled microtubule fraction while one additional MAP becomes evident. This new MAP is a phosphoprotein whose appearance is independent of protein synthesis. Four additional MAPs also become phosphorylated, and this phosphorylation is accompanied by a partial redistribution of MAPs into the unassembled soluble fraction. Stimulation of cells with purified platelet-derived growth factor or phorbol tumor promoter, a direct activator of protein kinase C, also induces phosphorylation of the same MAPs and DNA synthesis. These results demonstrate that activation of the protein kinase C pathway is sufficient to promote the phosphorylation of MAPs and mitogenesis. However, epidermal growth factor, which does not activate protein kinase C, also stimulates phosphorylation of MAPs and DNA replication. Furthermore, down-regulation of the protein kinase C pathway does not prevent these responses. We conclude that phosphorylation of MAPs and mitogenesis can proceed through protein kinase C-dependent and -independent pathways in 3T3 cells.

Animals↗
PubMed2005

Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22.

Bone mineral density (BMD) is a complex trait with a strong genetic component and an important predictor of osteoporotic fracture risk. Here we report the use of a cross-species strategy to identify genes that regulate BMD, proceeding from quantitative trait mapping in mice to association mapping of the syntenic region in the human genome. We identified a quantitative trait locus (QTL) on the mouse X-chromosome for post-maturity change in spine BMD in a cross of SAMP6 and AKR/J mice and conducted association mapping of the syntenic region on human chromosome Xp22. We studied 76 single nucleotide polymorphisms (SNP) from the human region in two sets of DNA pools prepared from individuals with lumbar spine-BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3100 post-menopausal women. This procedure identified a region of significant association for two adjacent SNP (rs234494 and rs234495) within the Xp22 locus (P<0.001). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (P=0.018) and genotypes (P=0.008). Analysis of rs234494 and rs234495 in 1053 women derived from the same population who were not selected for BMD values showed an association with LS-BMD for rs234495 (P=0.01) and for haplotypes defined by both SNP (P=0.002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach.

Absorptiometry, Photon↗
PubMed1994

Stable expression of heterologous microtubule-associated proteins (MAPs) in Chinese hamster ovary cells: evidence for differing roles of MAPs in microtubule organization.

To study the effects of microtubule-associated proteins (MAPs) on in vivo microtubule assembly, cDNAs containing the complete coding sequences of a Drosophila 205-kD heat stable MAP, human MAP 4, and human tau were stably transfected into CHO cells. Constitutive expression of the transfected genes was low in most cases and had no obvious effects on the viability of the transfected cell lines. High levels of expression, as judged by Western blots, immunofluorescence, and Northern blots, could be induced by treating cells with sodium butyrate. High levels of MAPs were maintained for at least 24-48 h after removal of the sodium butyrate. Immunofluorescence analysis indicated that all three MAPs bound to cellular microtubules, but only the transfected tau caused a rearrangement of microtubules into bundles. Despite high levels of expression of these exogenous MAPs and the bundling of microtubules in cells expressing tau, transfected cells had normal levels of assembled and unassembled tubulin. With the exception of the tau-induced bundles, microtubules in transfected cells showed the same sensitivity as control cells to microtubule depolymerization by Colcemid. Further, all three MAPs were ineffective in reversing the taxol-dependent phenotype of a CHO mutant cell line. The absence of a quantitative effect of any of these heterologous proteins on the assembly of tubulin suggests that these MAPs may have different roles in vivo from those inferred previously from in vitro experiments.

Animals↗
PubMed1993

Microtubule-associated proteins, MAP 1A and MAP 1B, interact with F-actin in vitro.

Microtubule-associated protein (MAP) 1 consisting of MAP 1A and 1B was purified from rat brain by the poly-L-aspartic acid (PLAA) method. We found that MAP 1 bound to F-actin in vitro up to a molar ratio of MAP 1 to actin monomers of 1:10. The apparent binding constant was about 2.7 x 10(7) M-1. In contrast to the binding of MAP 2 or tau to F-actin, the binding of MAP 1 to F-actin did not affect the low-shear viscosity of actin filaments. Binding experiments performed using fragments of MAP 1, obtained by chymotrypsin digestion, indicated that MAP 1 included binding domains to F-actin that were different from those in microtubules and also two light chains (31 and 29 kDa) that were cosedimented with F-actin as well as with microtubules.

Actins↗
PubMed2005

Activity-driven dendritic remodeling requires microtubule-associated protein 1A.

Activity-prompted dendritic remodeling leads to calcium-influx-dependent activation of signaling pathways within minutes and gene transcription within hours. However, dendrite growth continues for days and requires extension and stabilization of the cytoskeleton in nascent processes. In addition to binding microtubules, microtubule-associated proteins (MAPs) associate with the actin cytoskeleton, anchor ion channels and signaling complexes, and modulate synaptic growth. MAP2 is predominantly dendritic. MAP1B is at postsynaptic densities (PSD) and modulates ion channel activity, in addition to affecting axon growth. Less is known about MAP1A, but it is also enriched in dendrites at input locations, including PSDs where MAP1A associates with channel complexes and the calcium sensor caldendrin. MAP1A rescued hearing loss in tubby mice. Here we show that MAP1A becomes enriched in dendrites concurrently with dendritic branching and synapse formation in the developing brain; that synaptic activity is required for establishing mature MAP1A expression levels; and that MAP1A expression is required for activity-dependent growth, branching, and stabilization of the dendritic arbor.

Animals↗