A gene for premature ovarian failure associated with eyelid malformation maps to chromosome 3q22-q23.
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Adolescent↗
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MAPs in plant cells: delineating microtubule growth dynamics and organization.
Microtubule-associated proteins (MAPs) serve a wide variety of functions, from constructing and maintaining the microtubule cytoskeleton to using this cytoskeleton to transport cargo and to tether molecules that are involved in numerous cellular processes. Throughout the cell cycle, distinct microtubule arrays carry out specific roles in cytokinesis, karyokinesis, and cell expansion. Recent findings have shed new light on the importance of MAPs in controlling microtubule growth dynamics as well as in cross-linking microtubules to facilitate the formation and function of these cytoskeletal arrays.
Arabidopsis↗
Analysis of the primary sequence and microtubule-binding region of the Drosophila 205K MAP.
We have sequenced cDNA clones encoding the Drosophila 205K microtubule-associated protein (MAP), a protein that may be the species specific homologue of mammalian MAP4. The peptide sequence deduced from the longest open-reading frame reveals a hydrophilic protein, which has basic and acidic regions that are similar in organization to mammalian MAP2. Using truncated forms of the 205K MAP, a 232-amino acid region could be defined that is necessary for microtubule binding. The amino acid sequence of this region shares no similarity with the binding motif of MAP2 or tau. We also analyzed several embryonic cDNA clones, which show the existence of differentially spliced mRNAs. Finally, we identified several potential protein kinase target sequences. One of these is distal to the microtubule-binding site and fits the phosphorylation consensus sequence of proteins phosphorylated by the mitosis specific protein kinase cdc2. Our data suggest that the 205K MAP uses a microtubule-binding motif unlike that found in other MAPs, and also raise the possibility that the activities of the 205K MAP may be regulated by alternative splicing and phosphorylation.
Amino Acid Sequence↗
Survey for CAG repeat polymorphisms in the human MAP-2 gene.
Microtubule-associated protein-2 (MAP-2) expression is altered in response to a number of physiological insults such as Alzheimer's disease, schizophrenia, stroke and AIDS-dementia. Changes include alteration in MAP-2 transcription, translation, and state of phosphorylation. Multiple MAP-2 transcripts exist within the nervous system and, as noted for a number of genes expressed in the central nervous system, MAP-2 contains a region of trinucleotide repeats located in exon 1 of the 5' untranslated region (5' UTR). Since expansion of CAG repeats are found in several neurodegenerative disorders, we analysed the CAG repeats in MAP-2 for polymorphisms in 31 controls, 35 chronic schizophrenics, and 20 with other neuropsychiatric illnesses. Genomic DNA samples from 86 individuals were used as templates in PCR amplifications with primers within exon 1. Sequencing of the PCR products, or short tandem repeat polymorphism (STRP) analysis, demonstrated consistency in the size of the CAG repeats. This study demonstrates that the seven copies of the CAG repeat located in the 5' UTR of the MAP-2 gene are highly conserved in the general population, and that there is no evidence for expansion of the CAG repeat.
DNA↗
Cell cycle-dependent changes in the dynamics of MAP 2 and MAP 4 in cultured cells.
To examine the behavior of microtubule-associated proteins (MAPs) in living cells, MAP 4 and MAP 2 have been derivatized with 6-iodoacetamido-fluorescein, and the distribution of microinjected MAP has been analyzed using a low light level video system and fluorescence redistribution after photobleaching. Within 1 min following microinjection of fluoresceinated MAP 4 or MAP 2, fluorescent microtubule arrays were visible in interphase or mitotic PtK1 cells. After cold treatment of fluorescent MAP 2-containing cells (3 h, 4 degrees C), microtubule fluorescence disappeared, and the only fluorescence above background was located at the centrosomes; microtubule patterns returned upon warming. Loss of microtubule immunofluorescence after nocodozole treatment was similar in MAP-injected and control cells, suggesting that injected fluorescein-labeled MAP 2 did not stabilize microtubules. The dynamics of the MAPs were examined further by FRAP. FRAP analysis of interphase cells demonstrated that MAP 2 redistributed with half-times slightly longer (60 +/- 25 s) than those for MAP 4 (44 +/- 20 s), but both types of MAPs bound to microtubules in vivo exchanged with soluble MAPs at rates exceeding the rate of tubulin turnover. These data imply that microtubules in interphase cells are assembled with constantly exchanging populations of MAP. Metaphase cells at 37 degrees C or 26 degrees C showed similar mean redistribution half-times for both MAP 2 and MAP 4; these were 3-4 fold faster than the interphase rates (MAP 2, t1/2 = 14 +/- 6 s; MAP 4, t1/2 = 17 +/- 5 s). The extent of recovery of spindle fluorescence in MAP-injected cells was to 84-94% at either 26 or 37 degrees C. Although most metaphase tubulin, like the MAPs, turns over rapidly and completely under physiologic conditions, published work shows either reduced rates or extents of turnover at 26 degrees C, suggesting that the fast mitotic MAP exchange is not simply because of fast tubulin turnover. Exchange of MAP 4 bound to telophase midbodies occurred with dynamics comparable to those seen in metaphase spindles (t1/2 = approximately 27 s) whereas midbody tubulin exchange was slow (greater than 300 s). These data demonstrate that the rate of MAP exchange on microtubules is a function of time in the cell cycle.
Animals↗
Heat-stable microtubule protein MAP-1 binds to microtubules and induces microtubule assembly.
The microtubule-associated proteins, MAP-1, MAP-2 and tau, have been purified from brain tissue via a new approach using a heating step directly on the homogenate, followed by selective adsorption on calmodulin-Sepharose affinity columns and gel-filtration chromatography. Our results indicate that these MAPs share common biochemical properties, including heat stability, calmodulin binding and promotion of tubulin assembly into microtubules.
Animals↗
Modulation of protein kinases and microtubule-associated proteins and changes in ultrastructure in female rat pituitary cells: effects of estrogen and bromocriptine.
This study focused on the intracellular signal transduction system and microtubule-associated proteins (MAPs), such as MAP-2 and Tau protein. The modulation of these proteins and their correlation with ultrastructural changes were investigated in rat pituitary prolactin (PRL) cells. Adult female Wistar rats were treated with estrogen and bromocriptine and their pituitary glands were removed for analysis of the expression of tubulin, MAP-2, Tau protein, protein kinase C (PKC), and calcium calmodulin (CaM) kinase. Western blot analysis showed that estrogen increased and bromocriptine decreased the expression of PKC alpha, beta 1, beta 2, CaM kinase alpha, beta, MAP-2, and Tau protein. MAP-2 and Tau protein, which are cytosolic proteins, being translated on free ribosomes, were associated with the membrane of whirling rough endoplasmic reticulum (RER) in estrogen-treated cells and dissociated with vesiculated RER induced by bromocriptine. These results suggested that the modulation of MAP-2 and Tau protein may reflect changes of PKC and CaM kinase, and that the quantitative changes and intracellular modulation of MAPs induced by estrogen and bromocriptine, i.e., estrogen-induced association and bromocriptine-induced dissociation of MAP-2 and Tau protein with membrane of RER, may reflect the dynamics of microtubules and are associated with structural changes in the RER and changes in the synthesis and intracellular transport of PRL.
Animals↗
Correlates of methamphetamine use for Taiwanese adolescents.
The aim of the present study was to assess the associations between methamphetamine (MAP) use and psychiatric comorbidity, individual attitudes and personal knowledge of MAP use, family characteristics and peer factors in Taiwanese adolescents via a case-control study. Two hundred adolescent MAP users and 400 adolescent non-users were recruited. Their psychiatric comorbidity, attitudes and knowledge toward MAP use, family characteristics and peer interactions were assessed systematically. The associations between MAP use and those factors were examined by univariate and multivariate analysis. In conditional logistic regression analysis, comorbid conduct disorder, attitude favorable to MAP use and poor knowledge of MAP use, disrupted parenting, lower caregiver education level, having friends using or providing MAP and actively interacting with peers were associated significantly with MAP use. Adolescent MAP use was correlated with multiple factors that lie within individuals and the interaction with their family and peers. Correlates of MAP use identified in the present study may be helpful for the design and implementation of preventive intervention.
Adolescent↗
DNA loop domains in a 1.4-Mb region around the human hprt gene mapped by cleavage mediated by nuclear matrix-associated topoisomerase II.
We have mapped the positions in a approximately 1.4-Mb region of genomic DNA around the human hprt gene which are accessible in vivo to cleavage by topoisomerase II associated with the nuclear matrix. These positions, which are interpreted as the boundaries of DNA loop domains, were mapped in K562 cells by examining the truncation of rare-cutter restriction fragments separated by pulsed field gel electrophoresis after topoisomerase II-mediated cleavage, using seven linked markers mapped in this region as probes for indirect end-labeling. Eleven cleavage positions were detected and were interpreted as defining ten loop domains of lengths between 70 and 210 kb (average approximately 135 kb); the hprt gene resides in a 150-kb loop domain. Loop domain boundaries coincided with three of the fifteen deletion breakpoints mapped in a 600-kb sector of this region in human lymphocytes, within the limits of resolution of pulsed field gel electrophoresis; this correlation was not statistically significant.
Cell Nucleus↗
Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau.
The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer disease and accumulates in neurons undergoing neurofibrillary degeneration. In the present study, the associations of the Alzheimer-hyperphosphorylated tau (AD P-tau) with the high molecular weight MAPs (HMW-MAPs) MAP1 and MAP2 were investigated. The AD P-tau was found to aggregate with MAP1 and MAP2 in solution. The association of AD P-tau to the MAPs resulted in inhibition of MAP-promoted microtubule assembly. However, unlike the coaggregation of AD P-tau and normal tau, the association between AD P-tau and the HMW-MAPs did not result in the formation of filaments/tangles. The affinity of the tau-AD P-tau association was higher than that of HMW-MAPs-AD P-tau because normal tau inhibited the latter binding. The association between AD P-tau and the HMW-MAPs also appeared to occur in situ because these proteins cosedimented from the Alzheimer brain extracts, and, in the sediment, the levels of the HMW-MAPs correlated with the levels of AD P-tau. These studies suggested that the abnormally phosphorylated tau can sequester both normal tau and HMW-MAPs and disassemble microtubules but, under physiological conditions, can form tangles of filaments only from tau.
Alzheimer Disease↗
MAP2a, an alternatively spliced variant of microtubule-associated protein 2.
MAP2, a dendritically localized microtubule-associated protein (MAP), consists of a pair of high molecular mass (280 kDa) polypeptides, MAP2a and MAP2b, and several low molecular mass (70 kDa) proteins called MAP2c. Although MAP2b and MAP2c have been shown to arise via alternative splicing. It was not clear whether MAP2a is also created by alternative splicing or by posttranslational modification. Using epitope peptide mapping, we have demonstrated that an element specific to MAP2a is situated at its N-terminal end. A cDNA clone from an adult rat brain library was found to contain an additional 246 nucleotides situated at the 5' end of the 9-kb MAP2 mRNA. Antibodies generated against the encoded protein sequence recognize specifically MAP2a in rat brain homogenates. Moreover, although MAP2a, like MAP2b, is found in dendrites and cell bodies, its temporal appearance and cell type-specific distribution in rat brain differs from MAP2b.
Aging↗
Synthesis of putative microtubule-associated proteins by mouse blastocysts during early outgrowth in vitro.
The outgrowth of mouse trophoblast in culture provides a simplified model system analogous in certain ways to blastocyst implantation in vivo. Day-four blastocysts cultured for 3 days in vitro undergo extensive changes in cell shape and motility which are likely to involve the complex cytoskeletal system of the trophoblast cells. To explore the biochemical basis of these changes, one set of cytoskeletal proteins, the microtubule-associated proteins (MAPs), was studied. Day 4 blastocysts were labeled with [35S]methionine and blastocyst outgrowths, after 3 days in culture from the blastocyst stage, were labeled with [3H]methionine. Labeled embryos were disrupted and the soluble supernatants were pooled, and newly synthesized proteins from the two stages were coassembled with taxol-stabilized brain microtubule polymer enriched for MAP-binding sites. Double-labeled coassembly proteins (putative MAPS) were then released from the microtubule polymer by treatment with 0.35 M NaCl and analyzed by one-dimensional polyacrylamide gel electrophoresis. 3H/35S dpm ratios were determined for individual protein bands to compare the relative synthesis rates for day 4 blastocyst and day 3 outgrowth MAPs. In spite of the extensive changes in cell shape and motility associated with blastocyst outgrowth, a common set of putative MAPs characterizes the two stages investigated, including several in the size range of tau factors. No synthesis of high molecular weight MAPs comparable with MAP 1 or MAP 2 from brain was detected. The synthesis rates of individual MAPs relative to each other remain constant over this period and are likely coordinated with total protein and tubulin synthesis.
Alkaloids↗
MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains.
A novel Bax-associating protein, named MAP-1 (Modulator of Apoptosis), has been identified in a yeast two-hybrid screen. MAP-1 contains a BH3-like (BH: Bcl-2 homology) motif and mediates caspase-dependent apoptosis in mammalian cells when overexpressed. MAP-1 homodimerizes and associates with the proapoptotic Bax and the prosurvival Bcl-2 and Bcl-X(L) of the Bcl-2 family in vitro and in vivo in mammalian cells. Mutagenesis analyses revealed that the BH3-like domain in MAP-1 is not required for its association with Bcl-X(L) but is required for association with Bax and for mediating apoptosis. Interestingly, in contrast to other Bax-associating proteins such as Bcl-X(L) and Bid, which require the BH3 and BH1 domains of Bax, respectively, for binding, the binding of MAP-1 to Bax appears to require all three BH domains (BH1, BH2, and BH3) of Bax, because point mutation of the critical amino acid in any one of these domains is sufficient to abolish its binding to MAP-1. These data suggest that MAP-1 mediates apoptosis through a mechanism that involves binding to Bax.
Adaptor Proteins, Signal Transducing↗
A diabetes-associated T-cell autoantigen maps to a telomeric locus on mouse chromosome 6.
Identification of diabetes-associated T-cell autoantigens is important for understanding the immunopathology of diabetes and developing improved therapeutic strategies. We have used a genetic approach to move toward identifying the autoantigen recognized by a diabetogenic islet-specific T-cell clone from a nonobese diabetic (NOD) mouse. The unique antigen recognition pattern of this clone was utilized to map the gene encoding the antigen (or its expression) by genetic linkage analysis. In vitro analysis of T-cell proliferation by this clone showed that the capacity of the islets to stimulate T cells segregates as a single codominant gene in BALB/cByJ x (BALB/cByJ x NOD/Bdc) backcross mice. This phenotype was tightly linked to two microsatellites in the telomeric region of mouse chromosome 6.
Animals↗
Bacterial contig map of the 21q11 region associated with Alzheimer's disease and abnormal myelopoiesis in Down syndrome.
We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in human chromosome 21q11-q21, encompassing the region of elevated disomic homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as well as the markers, which has shown a strong association with Alzheimer's Disease that has never been explained. The map contains 89 overlapping PACs, BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of 140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by cDNA selection, exon trapping, and/or global EST sequencing have been positioned onto the map, and the only two genes so far mapped to this cytogenetic region, STCH and RIP140 have been precisely localized. This work converts a further 10% of chromosome 21q into a high-resolution bacterial contig map, which will be the physical basis for the long-range sequencing of this region. The map will also enable positional derivation of new transcribed sequences, as well as new polymorphic probes, that will help in elucidation of the role the genes in this region may play in abnormal myelopoiesis and leukemia associated with trisomy 21 and Alzheimer's Disease.
Alzheimer Disease↗
A kindred with MYH-associated polyposis and pilomatricomas.
MYH-associated polyposis (MAP) is a recently described autosomal recessive form of familial adenomatous polyposis (FAP) associated with susceptibility to colorectal carcinoma (CRC). MAP is caused by biallelic inactivating mutations of the MYH gene, a component of the base excision repair (BER) machinery, whose dysfunction leads to an increase in the rate of G > T transversions following DNA oxidative damage. MAP patients can present with either classic or attenuated polyposis. However, the MAP colonic and extracolonic phenotype has yet to be defined. We report on two siblings, born from consanguineous parents, who were found to be homozygotes for an MYH frameshift mutation. The propositus presented with a low number of colonic lesions and an early-onset CRC. Both siblings had a history of pilomatricomas, benign tumors derived from hair follicles, in childhood. The findings presented provide further evidence of phenotypic variability in MAP, and suggest that multiple pilomatricomas may be a useful cutaneous marker of MAP.
Adenomatous Polyposis Coli↗
Immunocytochemical localization of microtubule-associated proteins 1A and 2 in the rat retina.
We have studied the immunocytochemical localization of microtubule-associated proteins (MAPs) in rat retinal cells. Using biochemical and immunochemical methods we have identified microtubule-associated protein 1 (MAP1) and microtubule-associated protein 2 (MAP2) as major MAPs in the rat retina. With indirect immunofluorescence microscopy, the inner plexiform layer and the ganglion cell layer were stained with both anti-MAP1A antibody and anti-MAP2 antibody. Cells at the inner margin of the inner nuclear layer were prominently stained with anti-MAP2, but not with anti-MAP1A. Thin section-immunoelectron microscopy using colloidal gold-labeled secondary antibodies revealed MAP1A and MAP2 staining in the neuronal processes of the inner plexiform layer. A filamentous network between the microtubules in the neurites was stained with both antibodies. The developmental course of expression of MAP1A and MAP2 in rat retina was studied by indirect immunofluorescence microscopy. Although MAP2 was already present at 1 day postnatal, MAP1A was not detected until 7 days postnatal. These results indicate that: (1) retinal neurons are heterogeneous in their expression of MAPs; (2) retinal ganglion cells show the same intracellular distribution of MAP1A and MAP2 as typical nerve cells such as motor neurons; and (3) MAP1A and MAP2 are differentially expressed in developing rat retina.
Aging↗
Evidence for interhemispheric motor-level transfer in a simple reaction time task: an EEG study.
Simple visuomanual reaction time tasks require interhemispheric communication when stimuli are presented in the hemifield opposite the responding hand. Although confirmed in many studies, it is still a matter of debate when, at what functional level and at what site this interhemispheric transfer takes place. To address these questions, we recorded event-related potentials (ERPs) in 12 healthy subjects performing such a task and analyzed the data using techniques based on topographic ERP map characteristics. A method which has proved useful for associating ERP map configurations of different time periods with functional states of the brain was supplemented by a source localization procedure. The results suggest that transfer occurs late in time, on a functional motor level and at frontal sites, at least for left-to-right interhemispheric direction of transfer.
Adult↗