Microtubule-Associated Protein 1B, a Growth-Associated and Phosphorylated Scaffold Protein Beat M

Brain Research Bulletin 71 (2007) 541–558

Review Microtubule-associated protein 1B, a growth-associated and phosphorylated scaffold protein Beat M. Riederer a,b,∗ a Département de Biologie Cellulaire et de Morphologie (DBCM), Université de Lausanne, 9 rue du Bugnon, CH-1005 Lausanne, Switzerland b Centre des Neurosciences Psychiatriques (CNP), Hôpital Psychiatrique, 1008 Prilly, Switzerland Received 20 October 2006; accepted 28 November 2006 Available online 27 December 2006

Abstract Microtubule-associated protein 1B, MAP1B, is one of the major growth associated and cytoskeletal proteins in neuronal and glial cells. It is present as a full length protein or may be fragmented into a heavy chain and a light chain. It is essential to stabilize microtubules during the elongation of dendrites and neurites and is involved in the dynamics of morphological structures such as microtubules, microfilaments and growth cones. MAP1B function is modulated by phosphorylation and influences microtubule stability, microfilaments and growth cone motility. Considering its large size, several interactions with a variety of other proteins have been reported and there is increasing evidence that MAP1B plays a crucial role in the stability of the cytoskeleton and may have other cellular functions. Here we review molecular and functional aspects of this protein, evoke its role as a scaffold protein and have a look at several pathologies where the protein may be involved. © 2006 Elsevier Inc. All rights reserved.

Keywords: Microtubules; Actin; Cytoskeleton; Scaffold; MAP1B

Contents

1. Introduction ...... 542 1.1. MAP1B discovery ...... 542 2. Molecular aspects ...... 542 2.1. Molecular particularities ...... 543 2.2. Turnover ...... 543 2.3. Axonal transport ...... 544 2.4. MAP1B upstream regulation ...... 544 2.5. Structural homologies and similarities...... 544 2.6. Genetically modiﬁed animals ...... 544 2.7. Behavior of mutants ...... 545 3. MAP1B distribution ...... 545 3.1. MAP1B detection with antibodies ...... 545 3.2. MAP1B isolation ...... 545 3.3. MAP1B earliest expression ...... 545 3.4. Location and species ...... 545 3.5. MAP1B differences in the nervous system and in a variety of cells ...... 546 3.6. Subcellular particularities ...... 546

∗ Correspondence address: Departement´ de Biologie Cellulaire et de Morphologie (DBCM), Universite´ de Lausanne, 9 rue du Bugnon, CH-1005 Lausanne, Switzerland. Tel.: +41 21 692 5154; fax: +41 21 692 5105. E-mail address: [email protected].

4. MAP1B function and development ...... 546 4.1. Functional aspects ...... 546 4.2. MAP1B in regeneration ...... 547 5. MAP1B post-translational modiﬁcations...... 547 5.1. MAP1B polyglutamylation and glycosylation ...... 547 5.2. MAP1B phosphorylation ...... 548 5.3. Kinases using MAP1B as substrate ...... 548 5.4. MAP1B phosphorylation sites ...... 548 5.5. Protein phosphatases ...... 549 6. MAP1B regulation by various factors ...... 549 7. Is MAP1B a scaffold protein? ...... 549 8. MAP1B in pathology ...... 550 8.1. The fragile X mental retardation gene ...... 550 8.2. The giant axonal neuropathy ...... 550 8.3. Tuberous sclerosis ...... 550 8.4. MAP1B, aging and neurodegeneration ...... 550 8.5. Ischemia and stroke ...... 551 8.6. Convulsion and substances that inﬂuence MAP1B ...... 551 8.7. Dysplasia ...... 551 8.8. Schizophrenia ...... 551 8.9. MAP1B and cancer ...... 551 8.10. Congenital dyserythropoietic anemia...... 551 8.11. Spinal muscular atrophy (SMA) ...... 551 8.12. Vitreoretinopathy ...... 551 9. Conclusion and outlook ...... 551 References ...... 552

1. Introduction is associated with MAP1B and named MAP1B light chain, MAP1B-LC1 [111]. At birth, MAP1B is highly abundant in In neurons, the cytoskeleton is essential for the organization brain and decreases in concentration with progression of postna- and maintenance of shape and cellular function. This includes tal development. The essential role of MAP1B in neuritogenesis axonal transport, regional specialization and synaptic function. has been proven in different in vitro and in vivo models, as The cytoskeleton of nerve cells consists of morphologically reviewed previously [79]. Very soon, it was shown that MAP1B and biochemically well defined structures such as microtubules, has the ability to promote microtubule assembly [164,177], neurofilaments and microfilaments. Furthermore, brain spectrin that it is one of the first MAPs to appear in neuroblasts and (fodrin) and actin filaments constitute a membrane-associated essential for differentiation and growth of neuronal processes cytoskeleton. These structures are composed of several proteins, [24,176,224]. MAP1B is involved in the early axonal outgrowth that exhibit temporal, cellular- and subcellular-specific appear- and therefore essential in establishing the neuronal polarity ance during neurogenesis, differentiation and maturation. Here [78,87,126]. Furthermore, MAP1B, MAP2 and tau play some we will focus on microtubule-associated protein 1B (MAP1B), synergistic role in neurite outgrowth. MAP1B controls direction- its molecular composition, its function in the set-up of neu- ality of growth cone migration, while neurons that lack MAP1B ronal morphology and its role during neurite outgrowth, this was are characterized by increased terminal and collateral branching in parts previously reviewed [78,87,223]. Furthermore, some and impaired turning of growth cones [21,67,78,208]. Phospho- recent findings are discussed how this molecule interacts with a rylation of MAP1B is involved in modulation of microtubule variety of proteins and cellular elements and we will highlight stability and turning of growth cones [124,129] and interacts its role in several diseases [79,88,224]. with microfilaments [163,217].

1.1. MAP1B discovery 2. Molecular aspects

In the mid eighties MAP1B was discovered as one of three MAP1B is a large protein with an apparent molecular weight high molecular weight MAP1 forms. It is considered a major (Mr) between 320 and 330 kDa and a calculated molecular mass cytoskeletal protein and essential for neurite outgrowth. Inde- of 255,534 Da [145]. MAP1B is composed of 2464 amino acids. pendent studies named MAP1B also MAP1.2, MAP1x or MAP5 The microtubule binding domain of MAP1B contains a repeat [14,15,33,90,177]. It is the earliest embryonic brain MAP and sequence motif unrelated to that of tau and MAP2 with short present in axons, somata and dendrites [133,225,226].Itis motifs of KKEE or KKEVI and a set of 12 imperfect repeats especially abundant in developing axons. The C-terminal end of 15 amino acids each [145]. As outlined in Fig. 1, MAP1B of the MAP1B sequence comprises a smaller protein that has binding sites for microtubules and microﬁlaments. Cloning B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 543

Fig. 1. Restriction sites in the MAP1B genome (A) and the molecular organization of the full-length mouse MAP1B is represented (B) with its separion at around amino acid sequence 2100 into heavy and light chain. The restriction sites in panel A are essential to produce different MAP1B fragments, since it is difficult to work with the full-length molecule. In panel B different funtional sites are indicated: MAP1B is composed of 2464 amino acids. Actin binding (AB) sites, localize at the MAP1B-LC (2336–2459) and in the N-terminal domain of MAP1B-HC1-517. The tubulin binding site (MTB) of MAP1B is characterized by 21 KKEK repeats near the N-terminus (517–848) and comprises also a MTB in the MAP1B LC (2210–2336). In addition, a assembly-helping site MTA is found in the flanking region 9981–14401 helping to increase microtubule assembly [17]. A hydrophilic region (1866–2071) near the C-terminus contains 12 imperfect repeats (YSYETXEXTTXXPXX) as indicated as xxx in panel B. It is believed that not only the tubulin-binding site is involved in binding to microtubules. In addition, the MAP1B light chain has a self-interaction and can dimerize or oligomerize [217] as does the MAP1B-HC [38]. of cDNA encoding rat MAP1B and regulation of mRNA during with a cleavage site located near amino acid sequence 2100. development in different brain areas mRNA and protein lev- A microtubule binding domain (MTB) is localized near the els pattern are the same. Molecular cloning of MAP1A and N-terminal end of MAP1B-HC and a MTB is also present in MAP1B, revealed a single mRNA of 11kb for MAP1B. The the MAP1B-LC1 [91]. This indicates that the full length pro- MAP1B locus was located to the mouse chromosome 13, while tein has the capacity to cross-link microtubules as previously the MAP1A locus was found on chromosome 2; this clearly mentioned [191]. Nevertheless, cells transfected with the full indicated that MAP1A and 1B are structurally different proteins length MAP1B do not reveal excessive bundling of micro- and that they are expressed from separate genes [53,70]. The tubules [209]. LC3 is a subunit of MAP1A and variation in human gene was localized to the long arm of chromosome 15 LC composition may control the binding activity of MAP1A with sequence homologies between mouse rat and human at 90% and MAP1B to microtubules [127,128]. The MAP1B-LC1 is identity [114–116]. involved in microtubule stabilization, self-interaction and actin filament binding. MAP1B-LC1 stabilizes microtubules but such 2.1. Molecular particularities microtubules remain flexible. The LC1 harbors an actin-binding site that is homologous to the binding site found in MAP1A Several upstream consensus sequences include two TATA [217]. Differences in the composition of MAP1A, MAP1B and boxes that independently direct neuron-specific expression of LCs exist as different protein complexes and determine distinct a reporter gene [114]. There are two alternative and over- functional properties, in that MAP1B and LCs are essential dur- lapping promoters that direct neuron-specific expression of ing neuritogenesis, while MAP1A and LCs are more important the rat MAP1B gene and regulate the temporal and tissue- in mature neurons [146]. specific expression, one inducible and the other one constitutive [114–116]. This may also explain some of the differences in the 2.2. Turnover temporal, cellular and subcellular distribution. For the description of its molecular structure, its localization The turnover of cytoskeletal proteins in vivo was deter- and phosphorylation-dependent expression in developing neu- mined in 10-day-old rats by using [35S]methionine and by rons, two monoclonal antibodies were helpful [191]: MAP1B measuring the fast and slow decay rates, for MAP1B (5.8 appears as long filamentous molecule of 186 + 38 nm, it days ± 0.7/12.0 ± 1.3), for MAP2 (6.9 ± 0.3/12.4 ± 1.7), forms cross-bridges between microtubules with mainly phos- for tubulin (4.8 ± 0.5/15.0 ± 0.5) and for spectrin phorylated forms in axons and unphosphorylated forms (or (4.9 ± 0.4/16.0 ± 1.2), while the detergent insoluble NF- differentially phosphorylated forms) in soma and dendrites. H showed only a monophasic rate (18.5 days ± 1.5). The Its abundance in developing axons suggests that it plays an detergent insoluble MAP1B showed also a monophasic decay essential role in axonal elongation. MAP1B is encoded as a of 29.0 days ± 2.3 [186]. This suggests that part of MAP1B may polyprotein (full length MAP1B) and comprises the MAP1B be strongly associated with the detergent insoluble cytoskele- heavy chain (MAP1B-HC) and light chain 1 (MAP1B-LC1), ton. Proportions between MAP1B-LC1 and MAP1B–HC 544 B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 varies greatly between cells. The MAP1B-LC1: MAP1B-HC However, MAP1B and claustrin are structuraly and function- ratio in postnatal brain homogenates is between 6:1 and 8:1. aly not identical since only the N-terminal 1022 codons are Therefore, the MAP1B-LC1 has a greater half life than the utilized and encode the core protein of the extracellular proteo- MAP1B-HC, given that they are synthesized at a 1:1 ratio glycan claustrin and when the corresponding N-terminal part [135,136]. of MAP1B was expressed it bound to microtubules but did not localize in the extracellular matrix [216]. The Drosophila 2.3. Axonal transport FUTSCH/22C10 is a MAP1B-like protein required for dendritic and axonal development. It regulates synaptic microtubule orga- MAP1B moves along the axon together with slow compo- nization and is necessary for synaptic growth and structure [184]. nent a and b, at a speed of 7–9 mm/day. This transport rate The N- and C-terminal domains of Futsch are homologus to ver- comprises phosphorylated MAP1B, interestingly different phos- tebrate MAP1B, while the central domain is highly repetitive phorylation states move at different velocity with the slow axonal and shows sequence homologies to neurofilament proteins. The transport [122]. MAP1B is also involved in retrograde transport Futsch/22C10 is regulated by the fragile X-related gene, a gene of mitochondria [101]. During axonal development, MAP1B is responsible for mental retardation [254]. C190RF5 is a homo- characterized by a phosphorylation gradient that is increasing logue of MAP1B that interacts with a microtubule-stabilizer and towards the growth cone shaft [78,87,126]. Since the phospho- candidate tumor suppressor involved in the generation of can- rylation of MAP1B influences MAP1B binding to microtubules cer cells [117,118]. Coronin (Crn1) promotes rapid assembly it is feasible that differences in phosphorylation modify the trans- and cross-linking of actin filaments and actin to microtubules. port rate of MAP1B and variations may exist according to the Crn1 contains sequences homologous to MAP1B [82] that may phosphorylation state and location of MAP1B within the axon explain binding to microtubules. VCY2 is a testis-protein that or dendrites. locates in the Y chromosome. An interacting partner was identified by two-hybrid screen to be VCY2IP-1, a protein of 1059 2.4. MAP1B upstream regulation amino acids. Its sequence has 59.3% and 41.9% homology to MAP1B and MAP1A respectively, with large homologies The expression of MAP1B is under control of homeopro- with MAP1B at the N- and C-terminal ends [246]. The stroma tein transcription factors [64] and as already mentioned under membrane-associated protein 1 is involved in erythropoiesis and differential transcription [114,116]. The MAP1B promoter is contains similar repeats (KKD/E) as found in MAP1B [190]. regulated by the Engrailed homeoprotein in vivo [140]. A joint Dynein interacts with microtubules with an ATP-sensitive link- regulation of the MAP1B promoter by two overlapping home- age. Three clusters of contact of amino acids, two of which are oproteins HNF3beta/Foxa2 and Engrailed indicates a highly regions sharing sequence homology with MAP1B have been conserved mechanism for a direct interaction of homeoprotein identified. It is noteworthy that point mutations within these transcription factors. Transfection experiments in primary cul- regions weaken an interaction with microtubules [109]. tures demonstrated that Foxa2 antagonizes the Engrailed driven regulation of MAP1B[64]. The Hmob3 brain-specific sequence 2.6. Genetically modified animals is part of the human MAP1B gene 3UTR and encoded by a portion of the exon 7. Furthermore, two transcripts were iden- A lack of MAP1B in MAP1B null mutants suggests that tified, one for brain and one for kidney, while skeletal muscle the protein is implicated in the locally coordinated assembly comprises both transcripts [43]. The Dlx-2 homeobox gene con- of cytoskeletal components required for branching and straight trols neuronal differentiation and immature cells that contain Dlx directional axon growth [21]. The protein seems not to be essen- genes do express MAP1B and MAP2 but not the glial fibrillary tial for neuronal survival, but a disruption of the MAP1B gene acidic protein, GFAP [50]. This underlines, that an expression leads to a delayed development of the nervous system in mice of several MAPs, including MAP1B, is important for neuronal [207] or abnormal morphology of individual cells such as Purk- polarity and for setting the stage for synaptic connectivity. A inje cells and phenotypes with slower axonal growth rates, a differential transcription may also explain some of the discrep- lack of visual acuity, motor system abnormalities and variations ancies in MAP1B distribution in neurons and glia, differences in several brain areas such as olfactory bulb, hippocampus and in phosphorylation or between geneticaly modified mice. retina [54]. In a homozygous mutant mice with MAP1B dele- tion, suggest a role of MAP1B in axon guidance and polarity in 2.5. Structural homologies and similarities the central and peripheral nervous system [75,78,137]. Homozy- gous MAP1B −/− mice were viable but displayed absence of A sequence and structural homology to MAP1B has been corpus callosum and misguided myelinated fiber bundles and identified in claustrin and neuraxin [29,145,183,252] and more reduced number of myelinated larger axons [137]. Functional recently in the Drosophila Futsch/22C10 [98]. Claustrin, an redundancy of MAP1B and tau suggests some common action anti-adhesive neural keratan sulfate proteoglycan is structurally in the growth cone shaft, while MAP2 and MAP1B knock- related to MAP1B an inhibits cell adhesion. Claustrin has a high out mice point to a similar redundancy in dendritic growth sequence homology with an alternatively spliced 5 truncated [21,51,67,207,208,214], while MAP2-deficient mice behaved MAP1B fragment. It is expressed in chick brain, in cardiac and without apparent abnormalities. A different result was obtained smooth muscles and is found at high levels in astrocytes [29,30]. when MAP1B expression was deficient; mice died in their peri- B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 545 natal period, showing fiber tract malformation, disrupted cortical SMI31 staining persisted into adulthood [31]. This persistance patterning due to retarded neuronal migration and disrupted in staining is explained by a crossreactivity of this antibody laminar organization in the hippocampus and the cerebellum with neurofilament and tau proteins, that increases or persists, [74,77]. Cultured neurons from these mutant mice were charac- respectively, during maturation of brain tissue. Immunologicaly terized by a significant inhibition of axon formation, a delay in related proteins to MAP1B and MAP1A with Mr in the range neurite outgrowth, a reduced neurite elongation rate and inhib- of 160–220 kDa were identified during mouse spermatogene- ited microtubule bundling [75,80,214]. sis [71]. However, a sequence homology of these proteins with brain MAPs was not established. 2.7. Behavior of mutants 3.2. MAP1B isolation Gene targeting study revealed neuronal abnormalities and phenotypes with slower growth rates, lack of visual acuity, MAP1B was first isolated by affinity purification by using the motor system abnormalities and variations in several brain areas monoclonal antibody AA6, actually the same antibody that was including the olfactory bulb, hippocampus and retina [54]. The used for the identification of MAP5 [177]. In a large scale purifi- full length MAP1B is encoded by seven exons. Alternative tran- cation of bovine brain MAP1B, by using a two step ion exchange, scripts contain either exon 3A or 3U, and give rise to N-terminal a yield of 25–30 mg/kg MAP1B with a 95% purity was obtained truncated MAP1B (resembling those of MAP1A). Differences [165]. The isolation of recombinant MAP1B proofed difficult may explain some of the conflicting results obtained in MAP1B due to the large size of MAP1B [54]. Therefore, recombinant knockout mice [110]. The MAP1B gene has a highly conserved MAP1B need to be used. This is useful to define specific func- 4.3 kb 3 untranslated region [138]. Mice deficient of MAP1B tions for parts of the molecule or to produce sequence specific altered performance in behavioral phenotype. Impaired loco- polyclonal antibodies. motor activity, correlated with lack of physical endurance, but without significant differences in cognitive function and mem- 3.3. MAP1B earliest expression ory impairement [160]. An impaired hippocampal long-term potentiation (LTP) in MAP1B deficient mice and a rapid dephos- Although MAP1B is the earliest brain MAP in comparison phorylation after induction of LTP in MAP1B +/− mice, may to MAP1A, MAP2, or tau; none of these proteins was present in suggest some role in activity-dependent synaptic plasticity in the two cell stage of rat embryos [132]. Expression of MAP1B LTP [253]. occured during the initial pathfinding of olfactory receptor neurons in the mouse, by E10 [6]. MAP1B is also strongly expressed 3. MAP1B distribution in cells of the outer granular layer of the developing cerebellum, where neuroblasts undergo a last cell division before migrating 3.1. MAP1B detection with antibodies towards the inner granular layer and forming the parallel fibers [181]. MAP1B is concentrated in the distal region of growing Many monoclonal antibodies were used, differing in their axons, by several fold excess compared to proximal parts of reactivity with either phosphorylated epitopes, with a specific axons [13]. Many reports suggest that MAP1B and MAP1A conformational state of MAP1B, with modification indepen- are complementary in that MAP1B is essential during initial dent epitopes or with a species-specific sequences of MAP1B growth and during the maturation process is replaced by MAP1A [15,33,45,124,129,177,181,191,231]; in addition many poly- [223]. However, this is not always the case. The expression of clonal antibodies have been raised against specific recombinant MAP1A in the human fetal brain was found in two transient fragments of MAP1B. This variety of antibodies, with subtle or structures in the ganglion eminence of the telencephalic pro- great differences in their reactivity with MAP1B, in combina- liferative zone and the periretucular nucleus within the internal tion with molecular and species differences, with differences in capsule. MAP1A was present between 18 and 22 weeks of gesta- post-translational modification and temporal changes in expres- tion while MAP1B was found from the 26th week to the 33 week sion, with variations in location and modification make it very in the internal capsule [229]. MAP1B and MAP2 are present in difficult to compare and generalize results. The RT97 and SMI31 early embryonic spinal cord [154], this suggests that several antibodies with a crossreactivity with phosphorylated MAP1B brain structures differ in their maturation rate [155]. This com- were used to identify a stabilizing function of neurofilaments plentarity in function could also be explained by the formation and an interaction between neurofilaments and MAPs [199]. The of protein complexes with the same MAP1 light chains [146]. SMI31 monoclonal antibody reacts with a phosphorylated epitope comprised within a 20 amino acid region of MAP1B from 3.4. Location and species amino acids 1244–1264 [102]. The RT97, as also the SMI31 antibodies react with NF-H, NF-M, MAP1B and tau [200], therefore In one of the first comparative studies, several MAPs makes an interpretation of immunohistochemical data rather dif- were compared, and differences in distribution were high- ficult. The distribution of phosphorylated epitopes on MAP1B lighted for MAP1A, MAP2, MAP3 and MAP5 alias MAP1B in the developing rat spinal cord were studied with antibody 150 [133]. MAP1B was identified in many vertebrates as rat, that is reacting with mode I phosphorylated MAP1B and that mice, human, baboon, hamster, guinea pig, felines, bovine, detects MAP1B from E13 to the third postnatal week, while sheep, chicken, xenopus and fish and invertebrates such as flies 546 B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 and in trypanosomes [1,4,30,106,150,153,165,179,184,196, 224,229,240]. Interestingly the MAP1B expression in continuously growing fish follows the continuous development [1], suggesting that MAP1B expression is closely related to differentiation. MAP1B is expessed in the visual system of the tench during optic regeneration (fish) especially the phosphorylated form of MAP1B [239]. MAP1B (MAP5) is expressed and present as a phosphorylated form in the amphibian CNS of Xenopus, and was identified in the optic tectum to remain at high levels in adult animals [240]. During layer formation in the chicken optic tectum, MAP1B and NF-M appear at embryonic day 3, at a time of neuroblast production, while MAP1A and MAP2A&B are expressed later, at day E5 [251]. In a teleost fish, several MAPs were characterized: MAP1A and MAP2 were found of similar Mr, while MAP1B was about 25% of its Fig. 2. MAP1B and ␤-tubulin detection in a PC12 cell after 48 h in culture with mammalian homologue [218]. A 60% homology with MAP1B NGF. Note the differences in co-localization in the growth cone (insert). The was found in a 110 kDa protein of Trypanosoma brucei, and it arrow points to a branching area where MAP1B seems largely detached from was speculated to be one of the parasite molecules associated to microtubules and juxta posed next to microtubule bundles. molecular mimicry.

3.5. MAP1B differences in the nervous system and in a a recovery after antisense removal [25,176]. A chronological variety of cells expression of MAPs was observed in embryonal carcinoma P19 cells, induced by retinoic acid, in that MAP1B and MAP2c A differential regulation of MAP1B was found between the appeared 12 h after induction, while MAP1A and MAP2A/B rat central and peripheral nervous system development, in that appeared between 3 and 5 days [212]. MAP1B mRNA was highest in early stages, and decreases several fold in CNS but remained high in doral root ganlia of the PNS 3.6. Subcellular particularities [123]. It is evident that MAP1B is a developmentally regulated phospho-protein, with a pronounced decrease during postna- A MAP1B-related antigen localized to centrosomes seems tal development [185]. In adult brain, phosphorylated MAP1B involved in the organization of microtubule organizing cen- remained high only in a few areas including primary afferents ters [52]. Interestingly, a mitotic protein MPM-2, that increases and motor neurons, olfactory tubercles, habenular and raphe pro- the microtubule nucleation capacity of centrosomes con- jections to interpeduncular nuclei, septum and hypothalamus. tains sequences of the topoisomerase II and MAP1B [238]. Furthermore there was an overlap with N-CAM suggesting that Immunoreactivity with monoclonal antibody G10 is lost during MAP1B may play a role in the structural remodeling in adult brain homogenization [94], suggesting a reactivity with a spe- brain tissue [147,148]. cific conformational state of MAP1B. Localization of MAP1B in An expression and upregulation of MAP1B in retinal pig- postsynaptic densities of the rat cerebral cortex is found in about ment epithelial cells corresponds to the time when cells start to half of the total synapses [103]. MAP1B is a neuronal plasma lose epthelial characteristics and change their morphology [57]. membrane glycoprotein and co-localizes with the peri-axonal MAP1B is present in cultured oligodendrocytes and co-localizes region [213]. A specific binding of acidic phospholipids such as with tubulin but is absent from astrocytes [61]. Nevertheless, phosphatidylserine but not phosphatidylcholine to MAP1B reg- in glial cells of type 1 astrocytes, a specificaly phoshporylated ulates its interaction with tubulin pointing to a regulatory role MAP1B was found [234]. MAP1B expression precedes the in the MAP1B-microtubule interaction with biological mem- morphological differentiation of oligodendrocytes, as tested by branes [250]. MAP1B is a typical pohosphoprotein of growth development-specific oligodendrocyte antigens A2B5, O4 and cones [68,129], its location in growth cones of PC12 cells is O1. One of the low Mr forms of MAP2 was also transiently also demonstrated in the insert of Fig. 2. One should also note expressed in pre-oligodendrocytes [241]. MAP1B expression that part of MAP1B is not co-localizing with microtubules and was induced in Schwann cells during nerve regeneration, inter- may constitute a soluble pool of proteins or may relate to the estingly phosphorylation-dependent antibodies do not react with subcortical actin cytoskeleton (Fig. 3). this glial form of MAP1B [5]. This confirms that neurons and glia cells have different phosphorylation modes [234]. A human 4. MAP1B function and development cell line with a phenotype resembling committed CNS neuronal precursor cells (NT2/D1) expressed nestin, vimentin, MAP1B, 4.1. Functional aspects NCAM and N-cadherin and only small amounts of NF-L, alpha internexin, NF-M and MAP2c indicating neuronal fate [171]. MAP1B antisense oligonucleotides inhibits initiation of neu- MAP1B antisense treatment by oligonucleotides inhibits ini- rite outgrowth in NGF-treated PC12 cells with recovery after tiation of neurite outgrowth in NGF-treated PC12 cells with antisense removal [25]. By injecting polyclonal antibodies B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 547

MAPs, in that MAP1A microtubules were short and straight and MAP1B microtubules were longer and bendy [162]. Several studies suggest an overlapping in vivo role of tau with MAP1B in axonal stability, axon elongation and axon structure, suggesting some common functions of brain MAPs [21,67]. Expression of MAP1B was identiﬁed in actively myelinating oligodendrocytes in the adult rat brain [247]. A contact with astroglial membranes induces axonal and dendritic growth of CNS neurons with a common distribution of GAP43 and MAP1B [170], that also points to an interaction between glial and neuronal cells. The myelin associated glycoprotein, MAG, modulated expression and phosphorylation of MAP1B, NF-H and NF-M and increased activity of ERK1/2 and cdk5, while in mice lacking MAG the expression of MAP1B was decreased [40].

4.2. MAP1B in regeneration

MAPs plays an essential role in both, PNS development and regeneration and MAP1B undergoes a similar expression and modification as during postnatal development [149]. Its expression is induced in Schwann cells during nerve regeneration [121]. After lesions (peripheral and central) of trochlear motoneurons MAP1B expression was increased, this may reflect initial recapitulation of early development [19]. Partial regeneration and long-term survival of rat retinal ganglion cells after optic nerve crush, by increased MAP1B expression and phosphorylation with a gradient in phosphorylation towards Fig. 3. Co-transfection of COS-7 cells with SCG10 and MAP1B and triple- the soma of ganglion cells [48]. After percussion brain injury, immunostaining. (A) Combined fluorescence; (B) anti-MAP1B (Cascade blue); MAP1B and GAP43 are reexpressed and MAP1B phospho- (C) anti-SCG10 (Oregon green); (D) anti-tubulin (Texas red). Taken from rylation is increased, suggesting that these proteins are part Bondallaz et al. [17]. Note that SCG10 is more potent in the destruction of of a regeneration potential of neurons [56]. The two modes microtubules than MAP1B is in keeping an intact microtubule cytoskeleton. of MAP1B phosphorylation (as will be explained below in more detail) are differentially regulated during PNS regeneration in that mode I phosphorylation was concentrated against MAP1B into growing sympathetic neurons of rats and at distal region of nerves, while mode II phosphorylation mice an immunodepletion of MAP1B was induced, this did not showed an overall decrease in distal parts [174,175]. Target inhibit a robust axon growth, however, microtubules became deprived afferent fibers, after a kainic acid lesion in the adult more sensitive in the distal part of axons and in growth cones rat brain, induced MAP1B expression and its phosphoryla- when exposed to microtubule-destabilizing substances, such as tion. MAP1B phsphorylation seems essential since it allows nocodazole [215]. An increased microtubule stability and alpha- modulation of microtubule dynamics [202]. Phosphorylated acetylation of tubulin in cells transfected with MAP1B, MAP2 MAP1B is induced in central sprouting of primary affer- or tau was compared; a stabilization of microtubules was more ents in response to peripheral injury but not in response to effective with MAP1B than with MAP2c or tau when cells were rhizotomy. MAP1B was proposed as rapidly expressed, axon- exposed to microtubule destabilizing drugs [209]. Another study intrinsic marker associated with plasticity of myelinated fibers reported that MAP1B is weaker than MAP2 in its ability to sta- [203]. bilize microtubules when exposed to destabilizing conditions [237]. Nevertheless, these data all point to the fact that MAP1B 5. MAP1B post-translational modifications plays a microtubule stabilizing role [17]. The Futsch protein, a Drosophila homologue of MAP1B, is required for dendritic and 5.1. MAP1B polyglutamylation and glycosylation axonal development [98] and Futsch mutant flies show defects in microtubule loop domains similar to those one appearing in By blot overlay it was measured that polyglutamylation of collapsing growth cones [184]. The intermediate zone of the tubulin influences its binding to MAP1B, MAP2 and tau [18]. inferior ganlionic eminence constitutes an intermediate target MAP1B was identified to be a membrane glycoprotein and for growing axons, given that not all structures develop at the was localized as integral membrane protein in vesicles and the same pace it is evident that mature type proteins may appear plasma membrane of neurons [213]. Yet, most of the protein depending the state of maturation of a given structure [228]. may be associated with microtubules, actin filaments or may be A comparative study showed a modulation of microtubules by present in soluble form. 548 B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558

5.2. MAP1B phosphorylation cussed [255]; several upstream regulators such as semaphorins, and phosphatidylinositol 3-kinase, or neurotrophins and ERKs There is no doubt that phosphorylation of MAP1B plays a have been recognized. MAP1B phosphorylation is differentially crucial role for the modulation of MAP1B function as already regulated by cdk5, cdk5/p25 and JNK [104,158,169]. JNK1 is suggested by the first observations on (NGF) induced neu- required for the maintenance of neuronal microtubules and for rite outgrowth in PC12 cells [24,189,222]. MAP1B is strongly the control of MAP phosphorylation. Interestingly, Jnk−/− mice present in growing axons in developing brain tissue, in primary exhibit disrupted anterior commissure, a progressive loss of MTs neuronal cultures and in various cell lines with an increas- within axons and dendrites, and hypophosphorylated MAP2 and ing gradient of phosphorylated MAP1B towards the growth MAP1B [34]. A disrupted anterior commissure in Jnk−/− mice cones [13,23,32,86,89,105,232]. However, an outgrowth of neu- or a disrupted corpus callosum in Mab1b −/− mice may sug- rites may not necessarily depend on MAP1B phosphorylation gest that the presence of MAP1B and a specific phosphorylation [105,113]. type seem necessary for normal development of cortico-cortical projections. NMDA-glutamate receptors were found to regu- 5.3. Kinases using MAP1B as substrate late phosphorylation of dendritic cytoskeletal proteins in the hippocampus, including MAP1B and MAP2, thus confirming The research group of Jesus Avila identified two phospho- that they are involved in NMDA-dependent dendritic plasticity rylation types, a proline-dependent kinase (PDK) or mode I [188]. A phosphoryated MAP1B was found in neuroblast mito- phosphorylation in outgrowing axons and a Casein Kinase II sis [181].AM-Phase kinase in isolated spindles was identified to (CKII) or mode II phosphorylation in axons and dendrites use MAP4 and MAP1B as substrates. This kinase may be related remaining into adulthood [7,47,79,230]. The two modes regu- p34cdc2 [219]. Mitotic spindles contain also a CKII-like enzyme late also MAP1B phosphorylation during PNS regeneration, in that uses MAP1B as major substrate [46]; however this kinase cultured neurons [175,232] or in cell lines [93,166,210]. Mode has a rather subplasmamembrane location and may therefore I phosphorylation is development dependent and is reduced relate more to process outgrowth than to mitosis [141]. Phos- after the critical period of brain development, while mode II phorylation of MAP1B by an ecto-kinase suggests that MAP1B phosphorylation is present throughout postnatal development has a transmembrane domain and that MAP1B phosphorylation [175,178,179,224]. Phosphorylation of MAP1B by mode I is may relate to synaptogenesis between cortical neurons [144]. involved in the local stabilization of turning growth cones [124]. Yet, most data suggest that the large majority of MAP1B is In glial cells of type 1 astrocytes, only mode II phosphorylation localized in the cytoplasme and is associated with microtubules was found [234]. Cytosolic MAP1B is highly phosphorylated and/or microfilaments. by mode I and mode II during development, suggesting a lesser binding of MAP1B to microtubules [230] and also influencing 5.4. MAP1B phosphorylation sites its actin binding [163]. Several kinases have already been tested to phosphorylate MAP1B contains many potential phosphorylation sites with MAP1B such as CKII [141,231], cyclin-dependent kinases a downstream proline as targeting amino acid for PDKs, and as cdc2 and glycogen synthase kinase 3 [68,69,83,86,120] or many CKII target sites. In a proteomic study phosphorylated cdk5, cdk5/p25 and JNK [104,158]. Glycogen synthase kinase sites of many synaptic proteins were identified. MAP1B, is phos- 3β (CSK3␤) induced PC12 cell differentiation and modu- phorylated at 33 sites in vivo [36]. In summary, the GSK3␤ lates microtubule stability in growth cones [83,86,156], while is phosphorylating seven sites (S829, S1247, S1347, S1395, inhibitors of this kinase such as WNT7a, lithium and SB-216763 S1793, S1911, S2094), the cdk5 is phosphorylating eight sites induced axonal spreading and branching, a reduced axon elonga- (S829, S1260, S1317, S1334, S1610, S1621, S1775, S1793), tion rate, a change in growth cone morphology as characterized the cdc2 is phosphorylating two sites (S1768, S1775), the by an altered filopodia dynamic and microtubule distribution p38MAPK phosphorylates six sites (S1307, S1373, S1384, [120,156], and altered F-actin motility [13,84,86,156]. Reelin S1391, S1781, T1784) including one of the two threonine sites, is involved in the signaling cascade that leads to the MAP1B the CKII phosphorylates five sites (S828, S1307, S1382, S1768, mode I phosphorylation [76] and MAP1B is required for Netrin 1 S1877). Several kinases phosphorylate one or two sites, such as signaling in neuronal migration and axonal guidance via the sig- ERK1 (S1255) and PKG (T1806) with one site each and the PKA naling pathways including GSK3␤ and cdk5 [42]. The GSK3␤ with two sites (S1371, S1778). Most interestingly, a thyrosine phosphorylates mouse MAP1B at ser1260 and thr 1265 and is site (Y1331) is phosphorylated by INSR, src. In this study five spacially restricted to growing axons in a gradient that is high- predicted sites were mentioned including a DNA PK. Among est distally towards the growth cone [221]. The MAPK pathway phosphorylated sites only two sites localized in the microtubule is upstream of the activation of GSK3␤ that enables MAP1B binding region (517–848). No phosphorylation site of the C- phosphorylation and axonal growth [85] and is induced by terminal end and corresponding to MAP1B-LC1 was picked up growth factors and phorbol esters [97]. NGF activates the phos- in this study [36]. One wonders, wether the MAP1B-LC1 is not phorylation of MAP1B by GSK3␤ through the TrkA receptor present in growth cones or is not phosphorylated. This may also while an inhibition of the TrkA receptor inhibits neurite elon- signify that MAP1B is cleaved into HC and LC and the LC is gation [84]. The central role of GSK3␤, its signalling cascade metabolized before arriving into the growth cone or synapse. and its control of microtubule dynamics has recently been dis- Despite the fact that many phosphorylated sites have been iden- B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 549 tified, most functions of the phosphorylated sites remain largely link the microtubule bundles and organize actin filaments, this unknown. In addition, there must be more sites that are phospho- especially for MAP1B and MAP2 [41,163]. MAP1B may bind rylated since the SMI31 epitope is phosphorylated by GSK3␤ a variety of proteins either directly, or via tubulin and actin. Fur- at ser1260 and thr 1265 of mouse MAP1B [221]. Further- thermore, binding of proteins may differ between MAP1B HC more, several kinases that have been previously identified to and LC1. phosphorylate MAP1B were not picked up in this study. One Other proteins may interact with microtubule stability in has to consider that the identification of phosphorylated sites that they counteract the stabilizing effect of MAP1B, such as depends on the starting material, since MAP1B phosphorylation SCG10 a neuron specific protein of the stathmin family [182]. may change during develoment, and depend on various cues. MAP1B interacts with other proteins, such as gigaxonin, a pro- Phosphorylation of MAP1B changes during rat brain devel- tein that links microtubules and intermediate filaments and is opment and a structural microheterogeneity of MAP1B was involved in giant axonal neuropathy [16,49]. It may link a GABA speculated to be due to differences in phosphorylation [62]. receptor via the rho1 subunit to the cytoskeleton [12,92]. The One needs now to connect the specific phosphorylation sites to glycine transporter GLYT-1 associates with this protein com- specific functions. Why has MAP1B that many phosphorylated plex and is essential in neurotransmission in the retina [92,161]. sites? An interaction of MAP1B-LC1 with the glutamate receptor- interacting protein 1 (GRIP1) was identified by the yeast two 5.5. Protein phosphatases hybrid assay and suggests a novel mechanism for the AMPA receptors [197]. A G-protein coupled receptor is upregulated Dephosphorylation of distinct MAP1B sites such as mode by erythropoietin, interacts with MAP1B and colocalizes with I are dephosphorylated effectively by PP2A and PP2B but not the 5-hydroxytryptamine 2a receptor [134]. MAP1B may bind by PP1, while mode II are dephosphorylated by PP1 and PP2A myelin-associated glycoprotein (MAG) and seems to modulate but not by PP2B [233]. An inhibition of PP2A and 2B results expression and phosphorylation of MAP1B, NF-H and NF-M in inhibition of microtubule binding activity [72,73]. Ocadaic [40,65]. Given the large size of MAP1B one can expect to find acid (OA) was used to inhibit PP2A/PP1 and modulate MAP1B novel binding partners that add to the variety of its function as phosphorylation in neuroblastoma cells SY5Y. OA induced cell outlined in preliminary results [38]. Binding of heatshock pro- death and reduced microtubule stability [211]. tein 70 (hsp70) to the tubulin C-terminal sequence 431–444 was measured. The putative tubulin binding motif in the hsp70 pro- 6. MAP1B regulation by various factors tein contains a sequence related to the motif described in MAP1B [187]. MAP1B-LC1 binds to and enhances Rap1 activation and Angiotensin II and NGF influence MAP expression in PC12 it is attributed a chaperone activity [20]. Several proteins interact cells, while NGF increases MAP1B expression, Angiotensin with MAP1B and modulate microtubule dynamics: RASSF1A II is reducing it [205]. Activity-driven dendritic remodeling is active in the cell cycle and involved in growth inhibition requires MAP1B in postsynaptic densities and modulates ion of cancer cells [39]; the end binding protein-1 (EB1) comple- channel activity [206]. Agrin induced an increase in MAP1B ments MAP1B during axogenesis, overexpression of EB1 and expression, dendritic elongation and dendritic branching, while facilitates axogenesis in MAP1B −/− cells [100]; semaphorins in agrin depleted cultured hippocampal neurons extended longer function in the signaling cascade of growth cone collapse, in but non-branched axons and shorter dendrites [130]. Methyla- chemorepulsion, in neuronal apoptosis during early develop- zoxymethanol causes a long-term inhibition of axonal outgrowth ment and in an upregulation of MAPs [142,143]. Isolation of in cultured rat hippocampal neurons with a depletion of the sol- a multiprotein complex that contained MAP1B, CRMP-2, plex- uble MAP1B pool [96]. This substance causes microencephaly ins A1 and A2 and Sema3A is suggested to play a potential role and kills neuroblasts. Glucocorticoid at the dose used clinically in neurodegeneration and Alzheimer’s disease [81]. Coronin, alters cytoskeletal protein expression in that MAP1B expression Crn1 promotes rapid assembly and cross-linking of actin fil- was increased by 30% [4]. Betamethasone, a drug that is used to aments, links actin and microtubules and contains sequences accelerate fetal lung maturation has acute effects on cytoskele- that are homologous to MAP1B [82]. The Mapmodulin/leucine- tal proteins, for example: MAP1B was diminished in the frontal rich acidic nuclear protein binds the MAP1B-LC and modulates cortex of sheep [196]. The convulsant pentylenetetrazole leads to neuritogenesis [151]. MAP1B binds to lissencephaly-related a MAP1B upregulation in rat [242]. The substance panaxynol, protein 1 (LIS1), an interaction that interferes with LIS1-binding a polyacetylene with neurotrophic effects resulted in reduced to dynein and is regulated by the phosphorylation of MAP1B cell division of PC12 cells and in an upregulation of MAP1B [101]. This could be explained by the fact that dynein interacts [245]. with microtubules via an ATP-sensitive linkage, as mentioned before, via contacts that share some sequence homology with 7. Is MAP1B a scaffold protein? MAP1B [109]. An overexpression of the receptor tyrosine kinases Ror1 and Ror2 enhance extension of short and highly It has become clear by now that MAP1B is involved in branched processes, possibly regulated via MAP1B [157]. The a variety of cell functions. Therefore, the name microtubule- nuclear export factor (NFX1) of mRNA is able to bind MAP1B associated protein may be misleading. MAPs may be the missing and UNRIP in vitro and may be linked to microtubules via link between the actin and microtubule cytoskeleton in that they MAP1B [220]. 550 B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558

8. MAP1B in pathology and early-onset seizures. Lesions in the central nervous system consist of cortical tubers, subependymal glial nodules When analyzing brain tissue, one need to consider post and subependymal giant cell tumors. The neuron-like giant mortem effects, this is even more essential when the delay cells expressed strong immunoreactivity of neurofilament and between death and the collection of tissue depasses several MAP1B and occasionally nestin and vimentin and rarely GFAP. hours. Postmortem loss of MAP2 and MAP1B occurs within These cells show inconsistent neuronal and astroglial character- few hours after death, while tau proteins remained constant over istics, implying aberrant cellular differentiation [249]. a period of 8 h [195]. This becomes even more important when analyzing human brain tissue. One needs to consider that it 8.4. MAP1B, aging and neurodegeneration is impossible to obtain tissue form age-matched controls and patients with the same pharmacological background, disease, Calpain-mediated proteolysis of MAP1B and MAP2 in postmortem delay, age or cognitive evaluation. This means also developing brain is calcium-dependent and may be related to that studies for MAP1B in human diseases need to be studied by neurodegeneration [63]. The MAP1B signal was more abun- other studies than protein analysis of autopsy tissue. Naturally dant in early postnatal stages compared with mature animals. occurring human autoantibodies against MAP1B were identified In 24-months-old rats it was 1.7 times that of 6-months-old in sera of healthy persons, yet the clinical relevance is unclear rats [243]. In 18-month-old rats, MAP1B mRNA was very [168]. present and aberrant immunolabeling occurred in cortical layer VI. A loss of MAP1B and progressive loss of coordination 8.1. The fragile X mental retardation gene of gene activity could explain in parts the limited plasticity of the aging brain [244]. Fragments of phosphorylated MAP1B is implicated in fragile X mental retardation, in MAP1B are bound to neurofibrillary tangles in Alzheimer’s giant axonal neuropathy and in ataxia type 1 [152]. Frag- disease, while other studies did not find MAP1B in tangles ile X syndrome (mental retardation) mRNA co-localizes with [108] and one has to be careful in the interpretation due to MAP1B mRNA [3]. The fragile X protein (FMRP) con- some sequence homology of other proteins, or due to the pres- trols MAP1B translation and microtubule stability in brain ence of similar phosphorylation sites [95]. A fetal MAP1B neuron development. A lack of FMRP represses the trans- phosphorylation pattern is present in neurofibrillary degener- lation of MAP1B, while in FMRP KO mice microtubules ation in brains of Alzheimer’s disease. Both, MAP1B and tau are extremely stable, FMRP plays a critical role in con- proteins, may be subject to common phosphorylation, this dur- trolling cytoskeleton organization and normal development ing development and in disease, as was also shown for tau and microtubule dynamics is a conceivable underlying fac- proteins [180] and may control microtubule stability [235]. tor for the pathogenesis of fragile X mental retardation Alzheimer’s disease neurofibrillary tangles contain mitosis- [119]. The drosophila fragile X gene negatively regulates neu- specific phosphoepitopes, however MAP1B was not present ronal elaboration and synaptic differentiation. The disease is in the PHF fraction [108] and a dysfunction of tau is much caused by silencing the fmr1 gene; in turn this gene acts more prevalent [99]. Over expression of MAP1B full-length a negative translational regulator of Futsch/MAP1B. In con- but not the N-terminal truncated MAP1 accelerates apop- clusion, the fmr1 gene is central for neuronal architecture tosis of cultured cortical neurons. A␤amyloid is presumed and synaptic differentiation in the CNS and PNS of flies pathogenic in Alzheimer’s disease and induces aggregation [159]. especially of the 3U MAP1B transcript [227]. Estrogen-induced changes are beneficial in Alzheimer’s disease with a neuropro- 8.2. The giant axonal neuropathy tective effect, an increased pool of unstable microtubules and expression of juvenile MAPs such as MAP2C and MAP1B (GAN) is an autosomal recessive disorder, caused by muta- [198]. MAP1B and other MAPs (1A and 2) proteolysis is tions in GAN and characterized by cytoskeletal abnormalities. induced by amyloid beta peptide and involves calpain and cas- Yeast-two hybrid screening identified MAP1B-LC1 as bind- pase 3 both related to mechanisms in cell death [59]. The ing partner. Gigaxonin and MAP1B LC1 co-localized. GAN Drosophila homologue: FUTSCH/22C10 is a MAP1B-like pro- patients with two specific mutations in gigaxonin loos this inter- tein required for dendritic and axonal development. The N- action and consequently show axonal degeneration and neuronal and C-terminal domains of Futsch are homologous to verte- death [49]. Gigaxonin overexpression results in degradation brate MAP1B, while the central domain is highly repetitive of MAP1B-LC1, giant axonal neuropathy and neurodegener- and shows sequence homologies to neurofilament proteins [98] ation [2]. Intermediate filament aggregation in giant axonal and regulates synaptic organization and synaptic growth [184]. neuropathy patients crosstalk with intermediate filaments and The MAP1B homologue in flies, FUTSCH, is widely expressed microtubules [16]. in flies and in MAP1B knockout animals resulted in neurodegeneration and its relation to the drosophila fragile X mental 8.3. Tuberous sclerosis retardation gene needs to be mentioned again [11]. MAP1B (MAP5) was found in Lewy bodies and Lewy neurits in the brain Tuberous sclerosis is one of the most common neurocu- stem and forebrain regions from Parkinson’s disease patients taneous syndromes and characterized by mental retardation [66]. B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 551

8.5. Ischemia and stroke in the mammary glands of rats [112]. An accelerated neuronal differentiation with premature induction of MAP1B and dephos- Degeneration and regeneration after ischemia in aged rats phorylation of tau as a result of P53−/− KO might prevent was found with an upregulation of MAP1B [9]. After exper- neuronal terminal differentiation in neuroblasts and may be imental ischemia in rats, induced by photothrombic induction related to malignant cell growth [58]. and with postischemic intravenous BDNF application, improves functional motor recovery. A BDNF treatment induced MAP1B 8.10. Congenital dyserythropoietic anemia expression in the ischemic border zone [192]. A delayed recovery of MAP1B following stroke in aged rats was related to Congenital dyserythropoietic anemia (an inherited red blood MAP1B as a plasticity factor [8]. An upregulation of MAP1B cell disorder) is associated to changes in late erythroid pre- and MAP2 was measured after occlusion of the rat middle cere- cursors. The CDAN1 gene is encoding codanin-1 and is a bral artery [173]. This suggest that MAP1B is upregulated in an putative o-glycosylated protein with sequence homology in its attempt to repair or to regenerate the tissue. N-terminal part with collagens, with MAP1B (neuraxin) and with synapsin. Codanin-1 seems involved in nuclear envelope 8.6. Convulsion and substances that inﬂuence MAP1B integrity [44].

Pentylenetetrazole-induced seizure upregulates MAP1B in 8.11. Spinal muscular atrophy (SMA) the hippocampus of the rat [60]. MAP1B expression is increased in hippocampuss. subiculum and peroforant path with high doses In the ﬁne-mapping of the spinal muscular atrophy (SMA) of pentylenetetrazole [172]. This convulsant substance leads to locus, one uses the MAP1B intron sequence at the dis- robust long-term changes and upregulation in MAP1B [242] and tal ﬂanking region on chromosome 5q13. A closest linkage increased seizure susceptibility [194]. However, electroconvul- of the SMA and MAP1B locus is possible by using 5q13 sive shock induces an increase of MAP2 but nor of tau nor of microsatellite markers. However, MAP1B is not related to the MAP1B [167]. disease [26–28,35,55,125,139,193,204,236]. Prenatal diagnosis of SMA, via microsatellites diagnosis is useful also for the 8.7. Dysplasia Werdnig–Hoffmann disease [131].

MAP1B and nestin are enriched in neural progenitors and 8.12. Vitreoretinopathy abundant in neurons that populate the dysplastic regions with cytoarchitectonic abnormalities [37]. Early forms of MAPs are Vitreous treatment of cultured human retinal pigment epithe- strongly expressed in cortical dysplasia, especially MAP1B and lia results in reduced expression of several proteins, including MAP2c. Furthermore, an upregulation of the NMDA receptor MAP1B. A contact of epithelia cells with vitreous liquid may R1 suggests that activated excitatory structural remodeling of cause proliferative vitreoretinopathy [107]. Therefore, the eval- neuronal processes is activated by epileptic conditions in cortical uation of the MAP1B level may be important in the treatment dysplasia [248]. of the disease.

8.8. Schizophrenia 9. Conclusion and outlook

Postmortem olfactory mucosa of elderly schizophrenia MAP1B has first been identified with different antibodies, patients and controls revealed both dystrophic neurites, with- and it was soon recognized as major cytoskeletal protein dur- out differences in immunoreactivity of synaptophysin, MAP1B ing neurite outgrowth. The molecular characterization revealed and neurofilament proteins [201]. An increase in MAP2 and several forms of expression and post-translational modifications, MAP1B in schizophrenia and cytoarchitectonic abnormalities with phosphorylation as an effective means to change binding suggest some relation to the disease [10]. However, a decrease characteristics to structures such as microtubules or microfil- of MAP1B and MAP2 was measured in bipolar disorders, but aments and influence cellular dynamics. As growth-associated not in schizophrenia [22]. protein it takes an important part during neural development and in regeneration events. MAP1B is also involved in a vari- 8.9. MAP1B and cancer ety of diseases, but apparently in itself is not the cause for a specific disease. As a large molecule with many phosphoryla- RASSF1A interacts with MAP1B, modulates microtubule tion sites and separation into heavy and light chain, it provides dynamics in cell cycle and is involved in growth inhibition of many possibilities to interact with a variety of proteins. Despite cancer cells [39]. C190RF5 is a homologue of MAP1B that the fact that MAP1B has many phosphorylated sites, we still interactis with a microtubule-stabilizer and candidate tumor know little on the specific function of individual phosphory- suppressor RASSF1A [117,118]. Analysis of candidate genes lation sites. Indeed, from the recent literature it is emerging included in the mammary cancer susceptibility 1 (Mcs1) region that MAP1B can bind many other proteins and it seems there- in chromosome 2 (a region that expresses centromeric proteins), fore plausible that MAP1B forms a scaffold protein, between revealed among other proteins also MAP1B to be expressed cytoskeletal structures such as microtubules and microfilaments 552 B.M. Riederer / Brain Research Bulletin 71 (2007) 541–558 and membranes and may link functional proteins eventually in a [18] C. Bonnet, D. Boucher, S. Lazereg, B. Pedrotti, K. Islam, P. Denoulet, phosphorylation-dependent manner. There is also much to learn J.C. Larcher, Differential binding regulation of microtubule-associated how MAP1B is involved in the etiology of different pathologies. proteins MAP1A, MAP1B, and MAP2 by tubulin polyglutamylation, J. Biol. Chem. 276 (2001) 12839–12848. [19] A.A. Book, I. Fischer, X.J. Yu, P. Iannuzzelli, E.H. 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