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PubMed1998

Allelic association under map error and recombinational heterogeneity: a tale of two sites.

Recombination acts on the genetic map, not on the physical map. On the other hand, the physical map is usually more accurate. Choice of the genetic or physical map for positional cloning by allelic association depends on the goodness of fit of data to each map under an established model. Huntington disease illustrates the usual case in which the greater reliability of physical data outweighs recombinational heterogeneity. Hemochromatosis represents an exceptional case in which unrecognized recombinational heterogeneity retarded positional cloning for a decade. The Malecot model performs well for major genes, but no approach assuming either equilibrium or disequilibrium has been validated for oligogenes contributing to common disease. In this case of greatest interest, the power of allelic association relative to linkage is less clear than for major genes.

Alleles↗

PubMed1999

A new model for microtubule-associated protein (MAP)-induced microtubule assembly. The Pro-rich region of MAP4 promotes nucleation of microtubule assembly in vitro.

The microtubule-binding domains of microtubule-associated protein (MAP) 2, tau, and MAP4 are divided into three distinctive regions: the Pro-rich region, the AP sequence region and the tail region (Aizawa, H., Emori, Y., Murofushi, H., Kawasaki, H., Sakai., H., and Suzuki, K. (1990) J. Biol. Chem. 265, 13849-13855). Electron microscopic observation showed that the taxol-stabilized microtubules alone and those mixed with the A4T fragment (containing the AP sequence region and the tail region) had a long, wavy appearance, while those mixed with the PA4T fragment (containing the Pro-rich region, the AP sequence region, and the tail region) or the PA4 fragment (containing the Pro-rich region and the AP sequence region) were shorter and straighter. Stoichiometries of the binding between the fragments and the tubulin dimers were approximately between 1 and 2, suggesting that not all of the AP sequences in the AP sequence region bound to tubulin. Binding affinity of the PA4T fragment is only four times higher than that of the A4T fragment, while the microtubule nucleating activity of the PA4T fragment is far greater. Based on these results, we propose that the nucleation of microtubule assembly is promoted by the bridging activity of the Pro-rich region in the MAPs.

Binding Sites↗

PubMed1996

Plant microtubule-associated proteins (MAPs) affect microtubule nucleation and growth at plant nuclei and mammalian centrosomes.

In this study, we investigated the effect of plant microtubule-associated proteins (MAPs) on microtubule nucleation and growth in vitro. Since it has recently been demonstrated that plant nuclear surface acts as a microtubule-organizing center (MTOC), we tested the effects of plant MAPs using a nucleus-mediated microtubule nucleation assay. Nuclei were isolated from interphase tobacco BY-2 cells, and MAPs were isolated from tobacco BY-2 cells at different stages of the cell cycle. The effects of tobacco MAPs on microtubule nucleation at mammalian centrosomes were also analyzed. Under our experimental conditions, both interphase and mitotic tobacco MAPs promoted microtubule assembly around tobacco nuclei and at mammalian centrosomes below the critical tubulin concentration for spontaneous assembly. Interphase tobacco MAPs increase the mean length of nucleated microtubules in proportion to its molar ratio to tubulin. In contrast, mitotic tobacco MAPs do not induce nucleus- and centrosome-mediated nucleation of microtubules in a dose-dependent manner. Both MAP-fractions possessed microtubule bundling activity. The implications of these plant MAP properties on microtubule nucleation in living cells are discussed.

Animals↗

PubMed1987

An immunocytochemical analysis of the ontogeny of the microtubule-associated proteins MAP-2 and Tau in the nervous system of the rat.

The developmental distribution patterns of beta-tubulin and the microtubule-associated proteins, MAP-2 and Tau, were studied by immunocytochemistry with monoclonal antibodies. The analysis of the in situ distribution of these proteins in embryonic brain tissue revealed intense immunoreactivity for beta-tubulin in proliferative and migrating neuroblasts. On the contrary, no immunoreactivity for MAP-2 or Tau was detected in this neuroepithelium; specific immunostaining for these MAPs was only present in those neuroblasts which have reached their final destination within a developing brain area, and have initiated terminal differentiation, i.e. the sprouting of axons and dendrites. During the initial stages of neuritic outgrowth both MAPs were detected in the somatodendritic compartment of developing brain neurons; Tau was also present in axons. While the distribution of MAP-2 remained essentially the same throughout development, Tau was progressively lost from cell bodies and dendrites. This pattern of compartmentation was observed in pyramidal neurons of the cerebral cortex and hippocampus, as well as in cells of other brain regions (e.g. thalamus, hypothalamus, cerebral amygdala and tectum). It was not detected in cerebellar Purkinje cells which compartmentalize Tau to axons from the outset of neuritic differentiation, and in neurons of the Gasser ganglion which transiently express MAP-2 in axons. The expression and distribution of these MAPs was also analyzed in embryonic cerebellar and hippocampal pyramidal neurons grown in culture. Both MAPs were found in these cells as soon as 6 h after plating; they were also present in all of the neurites, axons and dendrites, that these cells extend after development in vitro for several days. With subsequence development (more than 4 days in vitro) MAP-2 was lost from axons, while Tau remained homogeneously distributed in both types of neurites. Taken collectively, the present results indicate that the development of the compartmentalized distribution of MAP-2 and Tau follows a complex pattern which is specific for each of these MAPs, and which varies as a function of the neuron type and the conditions under which the cell develops. In addition, the complex variations in the distribution of both MAPs during in situ and in vitro development make it unlikely that these proteins have a role in determining the fate of a neurite as an axon or a dendrite.

Animals↗

PubMed1991

Characterization of a new 120 kDa microtubule-associated protein (MAP) of rat brain.

A novel protein was identified in rat brain microtubules using a monoclonal antibody. The immunoreactive protein is a microtubule-associated protein (MAP) by the criteria of co-purification with tubulin through repeated cycles of microtubule polymerisation in vitro. It belongs to the class of thermostable MAPs and runs as a closely spaced polypeptide doublet of 120 kDa on SDS-PAGE gels. MAP-120 kDa is brain- and neuron-specific and is localized predominantly in Purkinje cell bodies and dendrites in the cerebellum and in dendritic compartments of pyramidal and granule neurons in the hippocampus and dentate gyrus. During postnatal brain development, MAP-120 kD levels increase about 3 to 4-fold.

Animals↗

PubMed1988

An immunocytochemical and biochemical study of the microtubule-associated protein MAP-2 during post-lesion dendritic remodeling in the central nervous system of adult rats.

A monoclonal antibody against the microtubule-associated protein MAP-2 was used to examine the fate of this molecule during post-lesion dendritic remodeling in the hippocampus and septum of adult rats. Qualitative and quantitative immunocytochemical analyses were carried out in the dentate gyrus after unilateral destruction of the entorhinal cortex (EC). An increase in MAP-2 immunoreactivity was detected in dendritic processes located in the outer 2/3 of the ipsilateral molecular layer (ML) 2 days after the lesion. whereas dendritic staining decreased considerably in the inner 1/3 of the same ML. The increase of staining was also detected 4, 6 and 8 days after the lesion; it was accompanied by an increase in the immunoreactivity in the inner 1/3 of the ML. After that period, a progressive decrease in anti-MAP-2 staining toward control levels was detected along the whole extent of the ipsilateral ML. This was concurrent with alterations in dendritic orientation, and a decrease in stained dendrites in the inner 1/3 of the ML. By 30 days post-lesion anti-MAP-2 staining was almost identical to that of the contralateral ML, although the alterations in dendritic morphology were still present in the ipsilateral ML. Changes in MAP-2 levels were also evaluated by densitometry of Western blots or dot immunobinding of hippocampal extracts obtained at different post-lesion intervals. The results obtained revealed a pattern of change in MAP-2 levels identical to that observed with the immunohistochemical stain. A similar, immunocytochemical and biochemical, analysis conducted in the lateral septal nucleus after unilateral transection of the fimbria showed no changes in the distribution and/or content of MAP-2 at any post-lesion interval analyzed (2, 10 and 20 days post-lesion). The present observations show that post-lesion dendritic remodeling is concurrent with modifications in the levels and distribution of MAP-2. These modifications suggest that the dendritic cytoskeleton is dynamically changing in response to perturbation of the synaptic environment. In addition, our results indicate that these changes may only occur in those neurons which have the capability to remodel their post-synaptic surface in response to deafferentation.

Animals↗

PubMed1994

Statistical analysis of the surface distribution of microtubule-associated proteins (MAPs) bound in vitro to rat brain mitochondria and labelled by 10 nm gold-coupled antibodies.

Purified mitochondria from rat brain were incubated in vitro which microtubule-associated proteins (MAPs) that are known to bind specifically on sites present on the outer membrane. The bound molecules were detected by immunoelectron microscopy and the linear distribution of the label along mitochondrial profiles was analyzed by statistical methods. The results demonstrate that gold-conjugated antibodies are distributed in a non-random fashion on the surface of mitochondria, suggesting regional concentrations of MAPs-binding sites. This finding argue for the existence of specialized domains on mitochondria that are involved in the association of the organelles to microtubules in situ.

Animals↗

PubMed1989

Cross-linking of microtubules by microtubule-associated proteins (MAPs) from the brine shrimp, Artemia.

Microtubules induced with taxol to assemble in cell-free extracts of the brine shrimp, Artemia, are cross-linked by microtubule-associated proteins (MAPs). When the MAPs, extracted from taxol-stabilized microtubules with 1 M-NaCl are co-assembled with purified Artemia or mammalian neural tubulin, reconstitution of cross-linking between microtubules occurs. The most prominent non-tubulin protein associated with reconstituted cross-linked microtubules has a molecular weight of 49,000 but we cannot yet exclude the possibility that other proteins may be responsible for the cross-linking. Cross-linkers are separated by varying distances while cross-linked microtubules, prepared under different conditions, are 6.9-7.7 nm apart. Cross-linking of microtubules by MAPs occurs whether MAPs are added to assembling tubulin or to microtubules, and it is not disrupted by ATP. The MAPs are heat-sensitive and do not stabilize microtubules to cold. Immunological characterization of Artemia MAPs on Western blots indicates that Artemia lack MAP 1, MAP 2 and tau. Our results clearly demonstrate that Artemia contain novel MAPs with the ability to cross-link microtubules from phylogenetically disparate organisms in an ATP-independent manner.

Alkaloids↗

PubMed2004

Ovine alpha-amylase genes: isolation, linkage mapping and association analysis with milk traits.

On the basis of comparisons between cattle and sheep genome mapping information the ovine alpha-amylase gene was examined as a possible genetic marker for milk traits in sheep. The objective of the present study was to isolate, map and determine whether this gene is a candidate gene for milk traits. DNA fragments (832 and 2360 bp) corresponding to two different AMY genes were isolated, and one SNP in intron 3 and one GTG deletion in exon 3 of the 2360 bp DNA fragment were found. The 2360 bp ovine AMY DNA fragment was located on chromosome 1 by linkage mapping using the International Mapping Flock. No association was found between estimated breeding values for milk yield, protein and fat contents and AMY genotypes in a daughter design comprising 13 Manchega families with an average of 29 daughters (12-62) per sire.

Animals↗

PubMed1997

Microtubule-associated proteins (MAPs) in the peripheral nervous system during development and regeneration.

In this article, we have described the structure and distribution of the various variants of the microtubule-associated proteins (MAPs), tau, MAP2, MAP1A, and MAP1B, that are expressed in the dorsal root ganglion (DRG) and spinal cord during development and regeneration. We have summarized the data on their gene structure and compared the sequence of the major transcripts encoding these MAPs that are expressed in the brain, the spinal cord, and the DRG. Finally, we have surveyed the studies that used a variety of experimental approaches (e.g., antisense inhibition, transgenic knockouts, and expression in neuronal and nonneuronal cells) to understand the functional significance of MAPs heterogeneity and differences observed between the central nervous system (CNS) and the peripheral nervous system (PNS) both during development and regeneration.

Alternative Splicing↗

PubMed1994

Activation of MAP kinase associated with the priming effect of LHRH.

A MAP kinase activity assay was developed to determine whether the LHRH receptor could activate this enzyme (particularly during LHRH priming). In anterior pituitary tissue from prooestrous rats LHRH caused concentration-dependent activation of MAP kinase after 5-10 min and continued for up to 60 min of incubation. The magnitude of this response correlated with that of LHRH priming on various days of the oestrous cycle but not with the magnitude of 1st hour (unprimed) LHRH-induced LH release. The response to LHRH was mimicked by a phorbol ester but not by ionomycin and was blocked with high potency by GF 109203X but not by H7 (in a similar manner to the PKC species that mediates LHRH priming). Neither the tyrosine kinase inhibitor lavendustin A nor the protein synthesis inhibitor cycloheximide blocked LHRH-induced MAP kinase activation. The possible functional significance of MAP kinase activation in gonadotrophs is considered with respect to LHRH priming.

Animals↗

PubMed1985

Microtubule-associated proteins (MAPs): a monoclonal antibody to MAP 1 decorates microtubules in vitro but stains stress fibers and not microtubules in vivo.

A monoclonal antibody (mAb 7-1.1) was produced against a bovine brain microtubule-associated protein (MAP) preparation that had been separated from tubulin after initial purification by cycles of microtubule assembly and disassembly in vitro. The antibody reacted specifically with two high molecular weight polypeptides of the MAP 1 class, designated MAP 1.1 and MAP 1.2, and also with the surfaces of MAP 1-containing microtubules that had been assembled in vitro. Double immunofluorescence microscopy using mAb 7-1.1 and a well-characterized rabbit anti-tubulin antibody revealed that mAb 7-1.1 stained stress fibers in fixed and permeabilized cultured mammalian cells rather than microtubules. The antibody also stained cell nuclei in a punctate fashion. mAb 7-1.1 is one of a number of monoclonal antibodies that react with presumptive MAP 1 polypeptides. Some of the MAP 1 antibodies have been found to bind specifically to microtubules in fixed and permeabilized cells, while others have been reported to react with nonmicrotubule structures. Our results, together with the results of other investigations, indicate that "MAP 1" may be a family of several high molecular weight polypeptides that adventitiously behave as MAPs by the criterion of in vitro coassembly with tubulin through cycles of polymerization and depolymerization but whose cellular distributions, and perhaps functions, are varied.

Animals↗

PubMed1989

Binding of microtubule-associated proteins (MAPs) to rat brain mitochondria: a comparative study of the binding of MAP2, its microtubule-binding and projection domains, and tau proteins.

Two major brain microtubule-associated proteins (MAPs), MAP2 and tau, were found to be able to bind to purified rat brain mitochondria. The apparent dissociation constants of the binding of thermostable 32P-labeled MAP2 and tau are 0.9 +/- 0.04 x 10(-7) and 3.8 +/- 0.7 x 10(-7) M, respectively. 32P-labeled MAP2 and tau bound to the mitochondria can be displaced by phosphorylated, nonradioactive MAP2. The binding parameters of MAP2 prepared without heat treatment and those of the thermostable MAP2 were of the same order of magnitude. Microtubule-binding and projection domains of MAP2 were obtained by chymotryptic digestion of rat brain microtubules (Vallee, Proc. Natl. Acad. Sci. USA, 77:3206-3210, 1980). Displacement studies with these two domains show that MAP2 bound to mitochondria can be displaced by the microtubule-binding domain, whereas the projection domain does not displace MAP2. The two domains of MAP2 bind to the mitochondria with similar affinity constants; however, the Bmax for the projection domain was 10 times and 35 times lower than the Bmax of the binding of the intact MAP2 and the microtubule-binding domain, respectively. Chymotryptic digestion of MAP2 bound to the mitochondria yielded peptide fragments with molecular masses similar to those obtained by the digestion of MAP2 bound to the microtubules. The fragments corresponding to the projection domain were released into the extramitochondrial supernatant, whereas the fragments originating from the microtubule-binding domain remained bound to the mitochondria. These results suggest that MAP2 binds to mitochondria preferentially via its microtubule-binding domain.

Animals↗

PubMed1985

Identification of microtubule-associated proteins (MAPs) in Xenopus oocyte.

Microtubules were isolated from prophase-blocked oocytes of Xenopus laevis with the use of the anti-tumor drug taxol. In addition to tubulin, 5 microtubule-associated proteins (MAPs) were characterized. Among them, 2 high molecular mass proteins (200-300 kDa) are phosphorylated in ovo. The oocyte MAP extract promotes the assembly of rat brain 6 S purified tubulin.

Alkaloids↗

PubMed1998

Male-associated polypeptide (MAP) expression in different compartments of the reproductive system of the mussel Mytilus galloprovincialis: immunocytochemical and western blot study.

Mytilus mussels are characterized by annually repeated reproduction which is associated with subsequent growth, morphogenesis, breakdown and redevelopment of the gonad and reproductive tract into mantle mesenchyme. We present a description of the expression of the male-associated polypeptide (MAP; see Mikhailov et al. 1995) in different compartments of the male reproductive system as well as in mantle gonad-supporting tissue. MAP is expressed in both gonad and mantle structures in dynamic patterns that show a substantial overlap in terms of dependence on the stage of gonad development/involution. In general, the total MAP concentration directly correlates with the volume of gonad tubule/duct structures but inversely correlates with mantle connective tissue cell fraction. A maximum of MAP expression is reached in the fully ripe male gonad. MAP is localized around gonad tubules/ducts, in the gonoduct epithelium, membranes of follicle-like structures as well as in the extracellular fiber-like structures of the mantle. However, we also demonstrate unique sites of MAP accumulation in the lumen of gonad follicle-like tubules and in ductal fluid. The latter is characterized by a very high MAP concentration. MAP is also detected in sperm-containing cell suspension obtained by gonad biopsy which we interpret as a result of the adsorption of MAP on mature spermatozoa. The results obtained should be taken into consideration in the interpretation of possible MAP functions since they seem to point to MAP as a major component of ductal (seminal) fluid of the male reproductive tract. It is likely that MAP is able to complement the processes of sperm terminal differentiation and maturation. In addition, we demonstrate that the male-predominant character of MAP expression is restricted by gonad-containing tissues (i.e., mantle and visceral mass) only, although the polypeptide is also detected in other somatic organs in both males and females.

Animals↗

PubMed2006

Bayesian method for gene detection and mapping, using a case and control design and DNA pooling.

Association mapping studies aim to determine the genetic basis of a trait. A common experimental design uses a sample of unrelated individuals classified into 2 groups, for example cases and controls. If the trait has a complex genetic basis, consisting of many quantitative trait loci (QTLs), each group needs to be large. Each group must be genotyped at marker loci covering the region of interest; for dense coverage of a large candidate region, or a whole-genome scan, the number of markers will be very large. The total amount of genotyping required for such a study is formidable. A laboratory effort efficient technique called DNA pooling could reduce the amount of genotyping required, but the data generated are less informative and require novel methods for efficient analysis. In this paper, a Bayesian statistical analysis of the classic model of McPeek and Strahs is proposed. In contrast to previous work on this model, I assume that data are collected using DNA pooling, so individual genotypes are not directly observed, and also account for experimental errors. A complete analysis can be performed using analytical integration, a propagation algorithm for a hidden Markov model, and quadrature. The method developed here is both statistically and computationally efficient. It allows simultaneous detection and mapping of a QTL, in a large-scale association mapping study, using data from pooled DNA. The method is shown to perform well on data sets simulated under a realistic coalescent-with-recombination model, and is shown to outperform classical single-point methods. The method is illustrated on data consisting of 27 markers in an 880-kb region around the CYP2D6 gene.

Alleles↗

PubMed1985

Microheterogeneity of microtubule-associated proteins, MAP-1 and MAP-2, and differential phosphorylation of individual subcomponents.

High molecular weight microtubule-associated proteins 1 and 2 (MAP-1 and MAP-2), prepared by copolymerization with tubulin, were electrophorectically separated into three and two major subcomponents, respectively, using 5% sodium dodecyl sulfate-polyacrylamide gels. By two-dimensional gel electrophoresis, all five MAP components were shown to possess a pI of around 5. Four of these proteins, MAP-1A, MAP-1C, MAP-2A, and MAP-2B, present in comparable amounts, were iodinated after electrophoretic separation and analyzed by two-dimensional peptide mapping. With both trypsin and V8 protease, almost identical patterns were obtained from MAP-2A and MAP-2B. MAP-1A and MAP-1C, too, gave similar digestion patterns, although some differences were noted. Incubation with [gamma-32P]ATP demonstrated that endogeneous protein kinase activities phosphorylated individual subcomponents at different rates. MAP-2A, the highest labeled component, was phosphorylated 2.5-fold compared to MAP-2B both in the presence and the absence of cAMP. Labeling of MAP-1 subcomponents was 4 times less than that of MAP-2A in the absence and 16 times less in the presence of cAMP. 32P-labeled MAP-2A and MAP-2B bands were indistinguishable by one-dimensional peptide mapping, as were the three MAP-1 bands. For both MAP-1 and MAP-2 subcomponents, cAMP induced phosphorylation at new molecular sites. Incubation of radiolabeled microtubule proteins with 1 mM ATP effected, upon electrophoresis, a clear shift of MAP-2A and MAP-2B bands to positions of higher apparent molecular weights, while only slightly affecting MAP-1 bands.

Adenosine Triphosphate↗

PubMed2005

[From gene to disease; MutYH-associated polyposis coli (MAP)].

MutYH-associated polyposis coli (MAP) is an autosomal recessive inherited form of polyposis and colorectal carcinoma associated with germline mutations in the MutYH gene on chromosome I. The MutYH protein is a base excision repair glycosylase which is involved in the repair of damage caused by the oxidation ofa guanine leading to 8-oxo-7,8-dihydroguanine. If the MutYH protein is dysfunctional, G:C --> T:A mutations in the APC-gene give rise to polyposis and in 50-60% of cases also colorectal carcinoma. MutYH polyposis differs from familial adenomatous polyposis coli in its mode of transmission, later age of onset, a less florid form of polyposis, and fewer extra colonic manifestations.

Adenomatous Polyposis Coli↗