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1.
MAP1B and MAP2 are major members of neuronal microtubule-associated proteins (MAPs). To gain insights into the function of MAP2 in vivo, we generated MAP2-deficient (map2(-/-)) mice. They developed without any apparent abnormalities, which indicates that MAP2 is dispensable in mouse survival. Because previous reports suggest a functional redundancy among MAPs, we next generated mice lacking both MAP2 and MAP1B to test their possible synergistic functions in vivo. Map2(-/-)map1b(-/-) mice died in their perinatal period. They showed not only fiber tract malformations but also disrupted cortical patterning caused by retarded neuronal migration. In spite of this, their cortical layer maintained an "inside-out" pattern. Detailed observation of primary cultures of hippocampal neurons from map2(-/-)map1b(-/-) mice revealed inhibited microtubule bundling and neurite elongation. In these neurons, synergistic effects caused by the loss of MAP2 and MAP1B were more apparent in dendrites than in axons. The spacing of microtubules was reduced significantly in map2(-/-)map1b(-/-) mice in vitro and in vivo. These results suggest that MAP2 and MAP1B have overlapping functions in neuronal migration and neurite outgrowth by organizing microtubules in developing neurons both for axonal and dendritic morphogenesis but more dominantly for dendritic morphogenesis. 相似文献
2.
MAP1B, a structural microtubule (MT)‐associated protein highly expressed in developing neurons, plays a key role in neurite and axon extension. However, not all molecular mechanisms by which MAP1B controls MT dynamics during these processes have been revealed. Here, we show that MAP1B interacts directly with EB1 and EB3 (EBs), two core ‘microtubule plus‐end tracking proteins’ (+TIPs), and sequesters them in the cytosol of developing neuronal cells. MAP1B overexpression reduces EBs binding to plus‐ends, whereas MAP1B downregulation increases binding of EBs to MTs. These alterations in EBs behaviour lead to changes in MT dynamics, in particular overstabilization and looping, in growth cones of MAP1B‐deficient neurons. This contributes to growth cone remodelling and a delay in axon outgrowth. Together, our findings define a new and crucial role of MAP1B as a direct regulator of EBs function and MT dynamics during neurite and axon extension. Our data provide a new layer of MT regulation: a classical MAP, which binds to the MT lattice and not to the end, controls effective concentration of core +TIPs thereby regulating MTs at their plus‐ends. 相似文献
3.
Bondallaz P Barbier A Soehrman S Grenningloh G Riederer BM 《Cell motility and the cytoskeleton》2006,63(11):681-695
In neurons, the regulation of microtubules plays an important role for neurite outgrowth, axonal elongation, and growth cone steering. SCG10 family proteins are the only known neuronal proteins that have a strong destabilizing effect, are highly enriched in growth cones and are thought to play an important role during axonal elongation. MAP1B, a microtubule-stabilizing protein, is found in growth cones as well, therefore it was important to test their effect on microtubules in the presence of both proteins. We used recombinant proteins in microtubule assembly assays and in transfected COS-7 cells to analyze their combined effects in vitro and in living cells, respectively. Individually, both proteins showed their expected activities in microtubule stabilization and destruction respectively. In MAP1B/SCG10 double-transfected cells, MAP1B could not protect microtubules from SCG10-induced disassembly in most cells, in particular not in cells that contained high levels of SCG10. This suggests that SCG10 is more potent to destabilize microtubules than MAP1B to rescue them. In microtubule assembly assays, MAP1B promoted microtubule formation at a ratio of 1 MAP1B per 70 tubulin dimers while a ratio of 1 SCG10 per two tubulin dimers was needed to destroy microtubules. In addition to its known binding to tubulin dimers, SCG10 binds also to purified microtubules in growth cones of dorsal root ganglion neurons in culture. In conclusion, neuronal microtubules are regulated by antagonistic effects of MAP1B and SCG10 and a fine tuning of the balance of these proteins may be critical for the regulation of microtubule dynamics in growth cones. 相似文献
4.
Microtubule-associated-protein 1b (MAP1b) is abundant in neurons actively extending axons. MAP1b is present on microtubules throughout growing axons, but is preferentially concentrated on microtubule polymer in the distal axon and growth cone. Although MAP1b has been implicated in axon growth and pathfinding, its specific functions are not well understood. Biochemical and transfection studies suggest that MAP1b has microtubule-stabilizing activity, but recent studies with neurons genetically deficient in MAP1b have not confirmed this. We have explored MAP1b functions in growing sympathetic neurons using an acute inactivation approach. Neurons without axons were injected with polyclonal MAP1b antibodies and then stimulated to extend axons. Injected cells were compared to controls in terms of axon growth behavior and several properties of axonal microtubules. The injected antibodies rapidly and quantitatively sequestered MAP1b in the cell body, making it unavailable to perform its normal functions. This immunodepletion of MAP1b had no statistically significant effect on axon growth, the amount of microtubule polymer in the axon, and the relative tyrosinated tubulin content of this polymer, and this was true in sympathetic neurons from rat, wild type mice, and tau knockout mice. Thus, robust axon growth can occur in the absence of MAP1b alone or both MAP1b and tau. However, immunodepletion of MAP1b significantly increased the sensitivity of microtubules in the distal axon and growth cone to nocodazole-induced depolymerization. These results indicate that MAP1b has microtubule-stabilizing activity in growing axons. This stabilizing activity may be required for some axonal functions, but it is not necessary for axon growth. 相似文献
5.
Jiménez-Mateos EM González-Billault C Dawson HN Vitek MP Avila J 《The Biochemical journal》2006,397(1):53-59
The MAPs (microtubule-associated proteins) MAP1B and tau are well known for binding to microtubules and stabilizing these structures. An additional role for MAPs has emerged recently where they appear to participate in the regulation of transport of cargos on the microtubules found in axons. In this role, tau has been associated with the regulation of anterograde axonal transport. We now report that MAP1B is associated with the regulation of retrograde axonal transport of mitochondria. This finding potentially provides precise control of axonal transport by MAPs at several levels: controlling the anterograde or retrograde direction of transport depending on the type of MAP involved, controlling the speed of transport and controlling the stability of the microtubule tracks upon which transport occurs. 相似文献
6.
MAP1B‐dependent Rac activation is required for AMPA receptor endocytosis during long‐term depression
Marion Benoist Rocío Palenzuela Carlos Rozas Patricio Rojas Elena Tortosa Bernardo Morales Christian González‐Billault Jesús Ávila José A Esteban 《The EMBO journal》2013,32(16):2287-2299
The microtubule‐associated protein 1B (MAP1B) plays critical roles in neurite growth and synapse maturation during brain development. This protein is well expressed in the adult brain. However, its function in mature neurons remains unknown. We have used a genetically modified mouse model and shRNA techniques to assess the role of MAP1B at established synapses, bypassing MAP1B functions during neuronal development. Under these conditions, we found that MAP1B deficiency alters synaptic plasticity by specifically impairing long‐term depression (LTD) expression. Interestingly, this is due to a failure to trigger AMPA receptor endocytosis and spine shrinkage during LTD. These defects are accompanied by an impaired targeting of the Rac1 activator Tiam1 at synaptic compartments. Accordingly, LTD and AMPA receptor endocytosis are restored in MAP1B‐deficient neurons by providing additional Rac1. Therefore, these results indicate that the MAP1B‐Tiam1‐Rac1 relay is essential for spine structural plasticity and removal of AMPA receptors from synapses during LTD. This work highlights the importance of MAPs as signalling hubs controlling the actin cytoskeleton and receptor trafficking during plasticity in mature neurons. 相似文献
7.
Nerve growth factor promotes reorganization of the axonal microtubule array at sites of axon collateral branching
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Mirela Spillane Farida Korobova Tatyana Svitkina Gianluca Gallo 《Developmental neurobiology》2015,75(12):1441-1461
The localized debundling of the axonal microtubule array and the entry of microtubules into axonal filopodia are two defining features of collateral branching. We report that nerve growth factor (NGF), a branch‐inducing signal, increases the frequency of microtubule debundling along the axon shaft of chicken embryonic sensory neurons. Sites of debundling correlate strongly with the localized targeting of microtubules into filopodia. Platinum replica electron microscopy suggests physical interactions between debundled microtubules and axonal actin filaments. However, as evidenced by depolymerization of actin filaments and inhibition of myosin II, actomyosin force generation does not promote debundling. In contrast, loss of actin filaments or inhibition of myosin II activity promotes debundling, indicating that axonal actomyosin forces suppress debundling. MAP1B is a microtubule associated protein that represses axon branching. Following treatment with NGF, microtubules penetrating filopodia during the early stages of branching exhibited lower levels of associated MAP1B. NGF increased and decreased the levels of MAP1B phosphorylated at a GSK‐3β site (pMAP1B) along the axon shaft and within axonal filopodia, respectively. The levels of MAP1B and pMAP1B were not altered at sites of debundling, relative to the rest of the axon. Unlike the previously determined effects of NGF on the axonal actin cytoskeleton, the effects of NGF on microtubule debundling were not affected by inhibition of protein synthesis. Collectively, these data indicate that NGF promotes localized axonal microtubule debundling, that actomyosin forces antagonize microtubule debundling, and that NGF regulates pMAP1B in axonal filopodia during the early stages of collateral branch formation. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1441–1461, 2015 相似文献
8.
Christian Gonzalez-Billault Jesus Avila Alfredo Cceres 《Molecular biology of the cell》2001,12(7):2087-2098
Cultured neurons obtained from a hypomorphous MAP1B mutant mouse line display a selective and significant inhibition of axon formation that reflects a delay in axon outgrowth and a reduced rate of elongation. This phenomenon is paralleled by decreased microtubule formation and dynamics, which is dramatic at the distal axonal segment, as well as in growth cones, where the more recently assembled microtubule polymer normally predominates. These neurons also have aberrant growth cone formation and increased actin-based protrusive activity. Taken together, this study provides direct evidence showing that by promoting microtubule dynamics and regulating cytoskeletal organization MAP1B has a crucial role in axon formation. 相似文献
9.
Dystonin is a large multidomain cytoskeletal-associated protein that plays an essential role in the nervous system. Loss of dystonin results in neuromuscular dysfunction and early death in a mouse mutant called dystonia musculorum. Conserved among related proteins, the plakin domain is a defining feature of all major dystonin isoforms, yet its interactions have not been explored in detail. The purpose of the present study was to identify novel interacting partners of the plakin domain of the neuronal isoform of dystonin (dystonin-a). Newly identified interacting proteins discovered through a pull-down assay were validated using coimmunoprecipitation, coimmunofluorescence, and proximity ligation assays. Microtubule associated protein 1B (MAP1B), a microtubule stabilizing protein, and clathrin heavy chain, the major component of the clathrin triskelion, were identified as interaction partners for dystonin-a. Increased levels of phosphorylated MAP1B suggest a misregulation of MAP1B and a potentially novel component of the dt pathology. This work will further facilitate our understanding of how cytoskeletal proteins can affect and regulate neurodegenerative disorders. 相似文献
10.
Microtubule-associated protein 1B function during normal development, regeneration, and pathological conditions in the nervous system 总被引:6,自引:0,他引:6
Gonzalez-Billault C Jimenez-Mateos EM Caceres A Diaz-Nido J Wandosell F Avila J 《Journal of neurobiology》2004,58(1):48-59
Microtubule-associated protein 1B is the first MAP to be expressed during the development of the nervous system. Several different approaches have revealed that MAP1B function is associated with microtubule and actin microfilament polymerization and dynamics. In recent years, the generation of molecular models to inactivate MAP1B function in invertebrates and mammals has sparked some controversy about the real role of MAP1B. Despite discrepancies between some studies, it is clear that MAP1B plays a principal role in the development of the nervous system. In this article, we summarize the evidence for MAP1B function in a wide variety of cellular processes implicated in the proper construction of the nervous system. We also discuss the role of MAP1B in pathological processes. 相似文献
11.
12.
Wang W Lundin VF Millan I Zeng A Chen X Yang J Allen E Chen N Bach G Hsu A Maloney MT Kapur M Yang Y 《PloS one》2012,7(4):e33094
In neurons, a highly regulated microtubule cytoskeleton is essential for many cellular functions. These include axonal transport, regional specialization and synaptic function. Given the critical roles of microtubule-associated proteins (MAPs) in maintaining and regulating microtubule stability and dynamics, we sought to understand how this regulation is achieved. Here, we identify a novel LisH/WD40 repeat protein, tentatively named nemitin (neuronal enriched MAP interacting protein), as a potential regulator of MAP8-associated microtubule function. Based on expression at both the mRNA and protein levels, nemitin is enriched in the nervous system. Its protein expression is detected as early as embryonic day 11 and continues through adulthood. Interestingly, when expressed in non-neuronal cells, nemitin displays a diffuse pattern with puncta, although at the ultrastructural level it localizes along the microtubule network in vivo in sciatic nerves. These results suggest that the association of nemitin to microtubules may require an intermediary protein. Indeed, co-expression of nemitin with microtubule-associated protein 8 (MAP8) results in nemitin losing its diffuse pattern, instead decorating microtubules uniformly along with MAP8. Together, these results imply that nemitin may play an important role in regulating the neuronal cytoskeleton through an interaction with MAP8. 相似文献
13.
Markus G?del Dunja Temerinac Florian Grahammer Bj?rn Hartleben Oliver Kretz Beat M. Riederer Friedrich Propst Stefan Kohl Tobias B. Huber 《PloS one》2015,10(10)
Podocytes are essential for the function of the kidney glomerular filter. A highly differentiated cytoskeleton is requisite for their integrity. Although much knowledge has been gained on the organization of cortical actin networks in podocyte’s foot processes, less is known about the molecular organization of the microtubular cytoskeleton in primary processes and the cell body. To gain an insight into the organization of the microtubular cytoskeleton of the podocyte, we systematically analyzed the expression of microtubule associated proteins (Maps), a family of microtubules interacting proteins with known functions as regulator, scaffold and guidance proteins. We identified microtubule associated protein 1b (MAP1B) to be specifically enriched in podocytes in human and rodent kidney. Using immunogold labeling in electron microscopy, we were able to demonstrate an enrichment of MAP1B in primary processes. A similar association of MAP1B with the microtubule cytoskeleton was detected in cultured podocytes. Subcellular distribution of MAP1B HC and LC1 was analyzed using a double fluorescent reporter MAP1B fusion protein. Subsequently we analyzed mice constitutively depleted of MAP1B. Interestingly, MAP1B KO was not associated with any functional or structural alterations pointing towards a redundancy of MAP proteins in podocytes. In summary, we established MAP1B as a specific marker protein of the podocyte microtubular cytoskeleton. 相似文献
14.
Kohei Arasaki Yuri Kurosawa Hana Kimura Naoki Nishida Naoshi Dohmae Akitsugu Yamamoto Shigeru Yanagi Yuichi Wakana Hiroki Inoue Mitsuo Tagaya 《EMBO reports》2018,19(8)
In fed cells, syntaxin 17 (Stx17) is associated with microtubules at the endoplasmic reticulum–mitochondria interface and promotes mitochondrial fission by determining the localization and function of the mitochondrial fission factor Drp1. Upon starvation, Stx17 dissociates from microtubules and Drp1, and binds to Atg14L, a subunit of the phosphatidylinositol 3‐kinase complex, to facilitate phosphatidylinositol 3‐phosphate production and thereby autophagosome formation, but the mechanism underlying this phenomenon remains unknown. Here we identify MAP1B‐LC1 (microtubule‐associated protein 1B‐light chain 1) as a critical regulator of Stx17 function. Depletion of MAP1B‐LC1 causes Stx17‐dependent autophagosome accumulation even under nutrient‐rich conditions, whereas its overexpression blocks starvation‐induced autophagosome formation. MAP1B‐LC1 links microtubules and Stx17 in fed cells, and starvation causes the dephosphorylation of MAP1B‐LC1 at Thr217, allowing Stx17 to dissociate from MAP1B‐LC1 and bind to Atg14L. Our results reveal the mechanism by which Stx17 changes its binding partners in response to nutrient status. 相似文献
15.
Ding J Valle A Allen E Wang W Nardine T Zhang Y Peng L Yang Y 《Biochemical and biophysical research communications》2006,339(1):172-179
Microtubule-associated proteins (MAPs) are critical regulators of microtubule dynamics and functions, and have long been proposed to be essential for many cellular events including neuronal morphogenesis and functional maintenance. In this study, we report the characterization of a new microtubule-associated protein, we named MAP8. The protein of MAP8 is mainly restricted to the nervous system postnatally in mouse. Its expression could first be detected as early as at embryonic day 10, levels plateau during late embryonic and neonatal periods, and subsequently decrease moderately to remain constant into adulthood. In addition to its carboxyl terminal binding site, the MAP8 polyprotein also contains a functional microtubule-binding domain at its N-terminal segment. The association of the carboxyl terminal of the light chain with actin microfilaments could also be detected. Our findings define MAP8 as a novel microtubule associated protein containing two microtubule binding domains. 相似文献
16.
《Developmental neurobiology》2017,77(4):493-510
Doublecortin‐like kinase 1 (DCLK1) is a member of the neuronal microtubule‐associated doublecortin (DCX) family and functions in multiple stages of neural development including radial migration and axon growth of cortical neurons. DCLK1 is suggested to play the roles in part through its protein kinase activity, yet the kinase substrates of DCLK1 remain largely unknown. Here we have identified MAP7D1 (microtubule‐associated protein 7 domain containing 1) as a novel substrate of DCLK1 by using proteomic analysis. MAP7D1 is expressed in developing cortical neurons, and knockdown of MAP7D1 in layer 2/3 cortical neurons results in a significant impairment of callosal axon elongation, but not of radial migration, in corticogenesis. We have further defined the serine 315 (Ser 315) of MAP7D1 as a DCLK1‐induced phosphorylation site and shown that overexpression of a phosphomimetic MAP7D1 mutant in which Ser 315 is substituted with glutamic acid (MAP7D1 S315E), but not wild‐type MAP7D1, fully rescues the axon elongation defects in Dclk1 knockdown neurons. These data demonstrate that DCLK1 phosphorylates MAP7D1 on Ser 315 to facilitate axon elongation of cortical neurons. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419–437, 2017 相似文献
17.
Zhen‐Yu She Ya‐Lan Wei Yang Lin Yue‐Ling Li Ming‐Hui Lu 《Biological reviews of the Cambridge Philosophical Society》2019,94(6):2033-2048
During cytokinesis, the organization of the spindle midzone and chromosome segregation is controlled by the central spindle, a microtubule cytoskeleton containing kinesin motors and non‐motor microtubule‐associated proteins. The anaphase spindle elongation 1/protein regulator of cytokinesis 1/microtubule associated protein 65 (Ase1/PRC1/MAP65) family of microtubule‐bundling proteins are key regulators of central spindle assembly, mediating microtubule crosslinking and spindle elongation in the midzone. Ase1/PRC1/MAP65 serves as a complex regulatory platform for the recruitment of other midzone proteins at the spindle midzone. Herein, we summarize recent advances in understanding of the structural domains and molecular kinetics of the Ase1/PRC1/MAP65 family. We summarize the regulatory network involved in post‐translational modifications of Ase1/PRC1 by cyclin‐dependent kinase 1 (Cdk1), cell division cycle 14 (Cdc14) and Polo‐like kinase 1 (Plk1) and also highlight multiple functions of Ase1/PRC1 in central spindle organization, spindle elongation and cytokinesis during cell division. 相似文献
18.
The aggregation of PrPSc is thought to be crucial for the neuropathology of prion diseases. A growing body of evidence demonstrates that the perturbation of the microtubule network contributes to PrPSc-mediated neurodegeneration. Microtubules are a component of the cytoskeleton and play a central role in organelle transport, axonal elongation and cellular architecture in neurons. The polymerization, stabilization, arrangement of microtubules can be modulated by interactions with a series of microtubule-associated proteins (MAPs). Recent studies have proposed the abnormal alterations of two major microtubule-associated proteins, tau and MAP2, in the brain tissues of naturally occurred and experimental human and animal prion diseases. Increased total tau protein and hyperphosphorylation of tau at multiple residues are observed at the terminal stage of prion disease. The abnormal aggregation of tau protein disturbs its binding ability to microtubules and affects the microtubule dynamic. Significantly downregulated MAP2 is detected in the brain tissues of scrapie-infected hamsters and PrP106–126 treated cells, which corresponds well with the remarkably low levels of tubulin. In conclusion, dysfunction of MAP2/tau family leads to disruption of microtubule structure and impairment of axonal transport, and eventually triggers apoptosis in neurons, which becomes an essential pathway for prion to induce the neuropathology. 相似文献
19.
《朊病毒》2013,7(4):334-338
The aggregation of PrPSc is thought to be crucial for the neuropathology of prion diseases. A growing body of evidence demonstrates that the perturbation of the microtubule network contributes to PrPSc-mediated neurodegeneration. Microtubules are a component of the cytoskeleton and play a central role in organelle transport, axonal elongation and cellular architecture in neurons. The polymerization, stabilization, arrangement of microtubules can be modulated by interactions with a series of microtubule-associated proteins (MAPs). Recent studies have proposed the abnormal alterations of two major microtubule-associated proteins, tau and MAP2, in the brain tissues of naturally occurred and experimental human and animal prion diseases. Increased total tau protein and hyperphosphorylation of tau at multiple residues are observed at the terminal stage of prion disease. The abnormal aggregation of tau protein disturbs its binding ability to microtubules and affects the microtubule dynamic. Significantly downregulated MAP2 is detected in the brain tissues of scrapie-infected hamsters and PrP106–126 treated cells, which corresponds well with the remarkably low levels of tubulin. In conclusion, dysfunction of MAP2/tau family leads to disruption of microtubule structure and impairment of axonal transport, and eventually triggers apoptosis in neurons, which becomes an essential pathway for prion to induce the neuropathology. 相似文献
20.
Going new places using an old MAP: tau, microtubules and human neurodegenerative disease 总被引:13,自引:0,他引:13
The microtubule-associated protein tau was originally identified as a protein that co-purified with tubulin in vitro, stimulated assembly of tubulin into microtubules and strongly stabilized microtubules. Recognized now as one of the most abundant axonal microtubule-associated proteins, a convergence of evidence implicates an overlapping in vivo role of tau with other axonal microtubule-associated proteins (e.g. MAP1B) in establishing microtubule stability, axon elongation and axonal structure. Missense and splice-site mutations in the human tau gene are now known to be causes of inherited frontotemporal dementia and parkinsonism linked to chromosome 17, a cognitive disorder of aging. This has provided direct evidence for the hypothesis that aberrant, filamentous assembly of tau, a frequent hallmark of a series of human cognitive diseases, including Alzheimer's disease, can directly provoke neurodegeneration. 相似文献