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Journal of Alzheimer’s Disease 40 (2014) S17–S22 DOI 10.3233/JAD-132315 IOS Press
Review
Crosstalk between Axonal Classical Microtubule-Associated Proteins and End Binding Proteins during Axon Extension: Possible Implications in Neurodegeneration a,b ´ C.L. Sayasa,b,1,∗ and Jes´us Avila a Centro
de Biolog´ıa Molecular “Severo Ochoa” (CSIC-UAM), Universidad Aut´onoma de Madrid, Campus de Cantoblanco, Madrid, Spain b Centro de Investigaci´ on Biom´edica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Accepted 26 December 2013
Abstract. During neuronal development, spherical neuroblasts differentiate into mature neurons through the extension of a long axon and several shorter dendrites. Morphological changes that underlie neuronal differentiation are mostly driven by the microtubular cytoskeleton. Regulation of microtubule dynamics and stability during axon and dendrite extension relies on the action of different families of microtubular proteins, such as classical microtubule-associated proteins (MAPs) and microtubule plus-end tracking proteins (+TIPs). This review article addresses recent research on the crosstalk between the main axonal MAPs, tau and MAP1B, and end binding proteins (EBs), the core +TIPs, during axon outgrowth in developing neuronal cells. Furthermore, we discuss the potential implications of the dysregulation of the interplay between tau and EBs in neurodegenerative disorders such as Alzheimer’s disease. Keywords: Alzheimer’s disease, axon outgrowth, MAPs, MAP1B, microtubule dynamics, neurodegeneration, neuronal development, tau, +TIPs
INTRODUCTION Neuronal development takes place following a complex program of morphological changes that gives rise to highly polarized neurons. Mature neurons possess two morphologically and functionally different types 1 Current address: Centro de Investigaciones Biom´ edicas de Canarias (CIBICAN), Universidad de La Laguna, Tenerife, Spain. ∗ Correspondence to: C.L. Sayas, Centro de Investigaciones Biom´edicas de Canarias (CIBICAN), Instituto de Tecnolog´ias Biom´edicas (ITB), Departamento de Anatom´ia, Facultad de Medicina, Campus de Ciencias de la Salud, Universidad de La Laguna, Tenerife, Spain. Tel.: +349229336; E-mails: [email protected]; [email protected].
of cytoplasmic extensions: a single axon, long and thin, which transmits signals, and multiple shorter dendrites, which receive signals. Deciphering the mechanisms that govern neuronal polarization and development is essential to understand synaptic transmission, plasticity, and neurodegeneration. Microtubule (MT) cytoskeleton is crucial for neuronal polarization, neurite and axon extension during neuronal differentiation. In mature neurons, MTs play an important role in the maintenance of cell shape and axonal transport. Hence, MT dynamics and stability have to be tightly regulated processes in both differentiating and adult neurons. Different types of interacting
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´ C.L. Sayas and J. Avila / Crosstalk between Axonal Classical Microtubule-Associated Proteins
proteins participate in the regulation of MT dynamics/stability in neurons [1]. Among them are classical structural MT-associated proteins (MAPs), which bind along the MT lattice and MT plus-end tracking proteins (+TIPs), which specifically accumulate at plus-ends of growing MTs. Recent reports indicate that these two types of microtubular proteins might act coordinately to regulate axon extension during neuronal development ([1], Sayas et al, unpublished data). We will discuss the possible consequences of the dysregulation of the functional interplay between the classical MAP tau and end binding proteins (EBs) in neurodegenerative disorders such as Alzheimer’s disease (AD). MT ORGANIZATION IN NEURONS In neurons, MTs form dense parallel fascicles (bundles) that are required for the growth and maintenance of axons and dendrites. These MTs are nucleated at the centrosome [2], released by the action of katanin, a MT-severing protein [3–5], and then transported as short polymers into neurites, axons, and dendrites by motor proteins [6, 7]. Besides MT transport, MT polymerization occurs in every neuronal compartment [8]. Organization of MTs differs between axons and dendrites in two major aspects: 1) axonal MTs present a uniform orientation, with their plus-ends facing the axon tip, whereas MT orientation in dendrites is mixed, with their plus-ends facing either the cell body or the dendritic tip; 2) the expression of MAPs is different, with MAP2 mostly found in dendrites and MAP1B and tau mainly present in axons [9]. Hence, it is possible to identify the type of cytoplasmatic extension based on the specific organization of the MTs present in each one. ROLES OF CLASSICAL MAPS IN NEURITE/AXON EXTENSION Classical or structural MAPs bind along MTs and stabilize them [10]. Tau and microtubule-associated protein 1B (MAP1B) are classical MAPs, mostly present in neurons [10]. MAP1B is the first MAP expressed, with highest expression levels during axon extension [11, 12]. Downregulation of MAP1B levels in the neonatal brain coincides with the completion of axonal extension and the initiation of active synaptogenesis [13]. This reduction in MAP1B protein levels is the consequence of a gradual decrease of MAP1B mRNA levels by the end of axonogenesis [14]. This process is regulated by the fragile X mental retarda-
tion protein (FMRP), which interacts with MAP1B mRNA and regulates its translation [14]. Contrary to MAP1B, tau expression levels and molecular complexity reach a peak upon synaptic formation and neuronal maturation [15–21]. Curiously, tau is a RNA binding protein but nothing is known about the regulation of tau mRNA translation in relation with its axonal expression. Both MAP1B and tau are direct MT regulators that promote MT nucleation, polymerization, and stabilization, in vitro and in vivo, but tau is a more potent MT stabilizer than MAP1B and induces MT bundling [22–25]. Both MAPs regulate also MT dynamics [26–29]. In cells, MAP1B is present both in cytosol and bound to dynamic MTs whereas tau mostly localizes along MTs, stabilizing them [22, 27]. In non-neuronal cells, ectopic expression of MAP1B enhances the population of dynamic MTs while tau overexpression induces extension of neuritelike protrusions and MT stabilization through the formation of bundles [16, 27]. In developing neurons, MAP1B and tau mainly localize in growing axons, particularly at their distal region [30, 31]. In line with their localization, both MAP1B and tau play important roles during neurite and axon extension. Downregulation of MAP1B or tau in neuron-like cells or primary neurons, using antisense oligos or by siRNA-mediated knockdown, leads to a delay in neurite/axon extension [32–36]. Hippocampal neurons from Map1b hypomorphous or TAU knockout mice present shorter axons than wildtype neurons [33, 37]. However, while tau-deficient mice are viable and do not present noticeable alterations in brain structure or behavioral deficits until they age [37–40], MAP1B-deficient mice show more dramatic phenotypes due to abnormal brain development that range from mild to severe (lyssencephaly-like), depending on the mice genetic background [41–44]. Mice deficient in both MAP1B and tau present more severe phenotypes related to brain development than tau-deficient mice [45].
ROLES OF EBS IN NEURITE/AXON EXTENSION MT plus-end tracking proteins (+TIPs) specifically accumulate at the plus-ends of growing MTs [46, 47]. +TIPs act as local regulators of MT dynamics and influence different dynamic instability parameters [46, 47]. +TIPs also provide a link between MT distal ends and actin, cell cortex, or organelles [46, 47].
´ C.L. Sayas and J. Avila / Crosstalk between Axonal Classical Microtubule-Associated Proteins
+TIPs are ubiquitous proteins, highly conserved among eukaryotes. +TIPs comprise a group of structurally unrelated proteins that range from motor proteins to MT polymerases/depolymerases, adaptor or regulatory proteins [46, 47]. Diverse +TIPs have been shown to play important roles during different stages of neuronal development such as migration, axon extension and guidance, dendritic spine formation, and maintenance of proper communication between neurons [48]. We will focus on the known roles of the family of EB proteins during neurite and axon extension. The EB protein family consists of three members (EB1-3) and is considered as the ‘core’ +TIP family [47], since EB1/3 track MT ends autonomously and mark all growing MTs [49–54]. Every known+TIP interacts with EB1/3 and many of them require EB1like proteins for plus-end tracking. Furthermore, many +TIPs interact with each other at MT plus-ends [47]. During neuronal development, EB1/3 are present in all neuronal compartments, indicating the existence of local MT polymerization throughout the neuron [8]. In differentiating neuroblastoma cells, EB1 regulates MT growth rate, growth distance, and duration and EB1 downregulation leads to reduction in neurite length [55]. Of the three family members, EB3 is predominantly expressed in brain, in particular in neurons [56]. EB3 is localized at the plus-ends of MTs that enter filopodia in advancing growth cones where it interacts with the F-actin-binding protein drebrin [57]. This interaction is crucial for the proper formation of growth cones and neurite extension. Of note, EB3 has also been found at growing ends of dynamic MTs that enter dendritic spines [58]. In spines, EB3 modulates actin dynamics through its interaction with p140Cap, a protein that binds the F-actin binding protein cortactin [58]. EB3 might act therefore as a linker between MTs and F-actin in neurons. In adult neurons, both EB1 and EB3 have been shown to be concentrated and stabilized in the axon initial segment (AIS), where they interact directly with the scaffold protein ankyrin G (ankG) [59]. EBs coordinate a molecular and functional interplay between MTs and ankG in the AIS [59]. Furthermore, EB1 is crucial for axonal targeting of potassium channel Kv1 (also enriched in the AIS), which regulate action potential propagation, an evolutionarily conserved function important for the control of motor behavior [60]. Therefore, EBs (EB1/3) function as local regulators of MT dynamics during neurite and axon outgrowth and play central roles in the maintenance of neuronal polarity through their actions on the AIS.
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FUNCTIONAL INTERPLAY BETWEEN AXONAL MAPS AND EBS DURING AXON OUTGROWTH MTs in neurites and axons are bundled into fascicles by the cross-linking action of MAPs, and on entering the growth cone they splay out with their plus-ends oriented distally [9]. EB1/3 accumulate at MT plusends in a comet-like pattern, in contrast with classical MAPs that bind along the MT lattice [47] (Fig. 1). The number of binding sites for EBs is higher at the very tip of MT distal ends and decays at a constant rate, leading to the typical comet-shape [47]. EBs undergo a fast exchange on/off MT growing ends [61]. Therefore, a pool of EB proteins exists in the cytosol and its interaction with MTs is susceptible to regulation. Our recent findings indicate that classical MAPs regulate EB1/3 localization and function during neurite and axon extension [1]. We showed that MAP1B overexpression displaces EBs from MT plus-ends whereas MAP1B downregulation enhances EB1/3 interaction with MTs [1]. In MAP1B-deficient neurons, the behavior of EB proteins is altered, leading to changes in MT dynamics [1]. This gives rise to MT overstabilization and looping in growth cones and contributes to growth cone remodeling and a delay in axon outgrowth in Map1b-/- neurons [1]. The effect of MAP1B on EB proteins is direct; MAP1B interacts with EB1/3 and sequesters them in the cytosol of elongating neurites/axons and growth cones of developing neuronal cells (Fig. 1a, b). In this way, MAP1B reduces the effective pool of cytosolic EBs that is available to interact with MT plus-ends and keeps MT highly dynamic during neurite/axon outgrowth. Of note, while EB1 levels remains constant, expression levels of tau and EB3 increase as neurons become mature and establish synaptic contacts [17, 58]. Our data indicate that tau exerts a different type of crosstalk with EB proteins in extending neurites/axons of differentiating neuronal cells (Sayas et al, unpublished data; Fig. 1a). In line with this, MAP2, another classical neuronal (dendritic) MAP that shares with tau conserved MT-binding repeats and an amino-terminal projection domain [62], has been shown to modulate the localization of EB3 [63]. MAP2 induces EB3 redistribution to MT bundles in a prolonged response to NMDA in dendrites of mature neurons [63]. From these studies, EBs emerge as key effectors of the actions of classical MAPs during axon extension. Thus, MAP1B and tau may act as local regulators of MT dynamics by modulating the localization and
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play between tau and EBs may still occur in adult neurons. In this context, it would be interesting to study whether hyperphosphorylated tau regulates the binding of EBs to MTs. If this is the case, the abnormal localization of tau in AD or tauopathies might lead to mislocalization of EB1/3 proteins in affected brains. Given that EBs are the main known regulators of MT dynamics [65], dysregulation of EBs distribution and function could further alter MT organization under pathological situations. As a consequence, many known EBs-interacting partners might also be mislocalized in AD or tauopathies. Misdistribution of the whole set of +TIPs, which normally form protein hubs at MT plus-ends, might have extra deleterious effects on MT architecture, and subsequently, on MT-dependent axonal transport. Research should be done to confirm whether a disruption of the crosstalk between tau and EBs occurs upon neurodegeneration and how it contributes to the pathology. CONCLUSIONS
Fig. 1. Interplay between axonal MAPs and +TIPs during neuronal development. In the axon shaft (a) and growth cone (b), MAP1B localizes along MTs and in the cytosol. MAP1B interacts directly with EB1/3 and sequesters them in the cytosol of extending axons and growth cones (a and b). Moreover, microtubular MAP1B displaces EB1/3 from the MT lattice. In this way, MAP1B contributes to keep MTs highly dynamic during neuronal differentiation. On the other hand, tau, which binds MTs and induces their bundling and stabilization (detail in a), crosstalks with EB1/3, regulating MT dynamics and stability during neuronal development.
function of EB1/3. Notably, MAP1B and tau regulate EBs in different manners indicating that their roles during axon extension are not overlapping, contrary to the general view.
The correct formation and proper function of the nervous system relies on the ability of neurons to polarize and undergo major morphological changes. Rearrangements of MT cytoskeleton underlie these changes in cell shape. MT assembly and dynamics are regulated by a plethora of proteins, such as classical MAPs and +TIPs [10, 46, 47, 64]. Recent findings indicate that axon extension is regulated by the coordinated actions of axonal MAPs (MAP1B and tau) and the core + TIPs (EBs) ([1], Sayas et al., unpublished data). From these studies MAPs have emerged as direct regulators of EBs localization and function during neurite and axon outgrowth. It remains to be elucidated whether the interplay between classical MAPs and EBs, or its disruption, contributes to neurodegeneration in disorders such as AD.
POSSIBLE IMPLICATIONS IN ALZHEIMER’S DISEASE
ACKNOWLEDGMENTS
Neurofibrillary tangles, a histopathological hallmark of AD, are composed of paired helical filaments made of hyperphosphorylated tau [20]. Abnormal tau hyperphosphorylation is also a hallmark of tauopathies, other related neurodegenerative disorders [64]. Since tau modulates the interaction of EBs with MTs during neuronal development (Sayas et al., unpublished data) and their levels remain high in adult neurons [17, 58], it is likely that the inter-
C.L. Sayas was supported by CSIC and CIBERNED (Madrid), and is currently supported by the IMBRAIN project. The authors would like to acknowledge the IMBRAIN project (FP7-REGPOT-2012-CT201231637-IMBRAIN), funded under the 7th Framework Programme (Capacities). This work was supported by grants from the Spanish Research Council (CSIC) (Plan Nacional), CIBERNED and Comunidad de Madrid (Spain).
´ C.L. Sayas and J. Avila / Crosstalk between Axonal Classical Microtubule-Associated Proteins
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2080).
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Journal of Alzheimer’s Disease 40 (2014) S17–S22 DOI 10.3233/JAD-132315 IOS Press
Review
Crosstalk between Axonal Classical Microtubule-Associated Proteins and End Binding Proteins during Axon Extension: Possible Implications in Neurodegeneration a,b ´ C.L. Sayasa,b,1,∗ and Jes´us Avila a Centro
de Biolog´ıa Molecular “Severo Ochoa” (CSIC-UAM), Universidad Aut´onoma de Madrid, Campus de Cantoblanco, Madrid, Spain b Centro de Investigaci´ on Biom´edica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Accepted 26 December 2013
Abstract. During neuronal development, spherical neuroblasts differentiate into mature neurons through the extension of a long axon and several shorter dendrites. Morphological changes that underlie neuronal differentiation are mostly driven by the microtubular cytoskeleton. Regulation of microtubule dynamics and stability during axon and dendrite extension relies on the action of different families of microtubular proteins, such as classical microtubule-associated proteins (MAPs) and microtubule plus-end tracking proteins (+TIPs). This review article addresses recent research on the crosstalk between the main axonal MAPs, tau and MAP1B, and end binding proteins (EBs), the core +TIPs, during axon outgrowth in developing neuronal cells. Furthermore, we discuss the potential implications of the dysregulation of the interplay between tau and EBs in neurodegenerative disorders such as Alzheimer’s disease. Keywords: Alzheimer’s disease, axon outgrowth, MAPs, MAP1B, microtubule dynamics, neurodegeneration, neuronal development, tau, +TIPs
INTRODUCTION Neuronal development takes place following a complex program of morphological changes that gives rise to highly polarized neurons. Mature neurons possess two morphologically and functionally different types 1 Current address: Centro de Investigaciones Biom´ edicas de Canarias (CIBICAN), Universidad de La Laguna, Tenerife, Spain. ∗ Correspondence to: C.L. Sayas, Centro de Investigaciones Biom´edicas de Canarias (CIBICAN), Instituto de Tecnolog´ias Biom´edicas (ITB), Departamento de Anatom´ia, Facultad de Medicina, Campus de Ciencias de la Salud, Universidad de La Laguna, Tenerife, Spain. Tel.: +349229336; E-mails: [email protected]; [email protected].
of cytoplasmic extensions: a single axon, long and thin, which transmits signals, and multiple shorter dendrites, which receive signals. Deciphering the mechanisms that govern neuronal polarization and development is essential to understand synaptic transmission, plasticity, and neurodegeneration. Microtubule (MT) cytoskeleton is crucial for neuronal polarization, neurite and axon extension during neuronal differentiation. In mature neurons, MTs play an important role in the maintenance of cell shape and axonal transport. Hence, MT dynamics and stability have to be tightly regulated processes in both differentiating and adult neurons. Different types of interacting
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´ C.L. Sayas and J. Avila / Crosstalk between Axonal Classical Microtubule-Associated Proteins
proteins participate in the regulation of MT dynamics/stability in neurons [1]. Among them are classical structural MT-associated proteins (MAPs), which bind along the MT lattice and MT plus-end tracking proteins (+TIPs), which specifically accumulate at plus-ends of growing MTs. Recent reports indicate that these two types of microtubular proteins might act coordinately to regulate axon extension during neuronal development ([1], Sayas et al, unpublished data). We will discuss the possible consequences of the dysregulation of the functional interplay between the classical MAP tau and end binding proteins (EBs) in neurodegenerative disorders such as Alzheimer’s disease (AD). MT ORGANIZATION IN NEURONS In neurons, MTs form dense parallel fascicles (bundles) that are required for the growth and maintenance of axons and dendrites. These MTs are nucleated at the centrosome [2], released by the action of katanin, a MT-severing protein [3–5], and then transported as short polymers into neurites, axons, and dendrites by motor proteins [6, 7]. Besides MT transport, MT polymerization occurs in every neuronal compartment [8]. Organization of MTs differs between axons and dendrites in two major aspects: 1) axonal MTs present a uniform orientation, with their plus-ends facing the axon tip, whereas MT orientation in dendrites is mixed, with their plus-ends facing either the cell body or the dendritic tip; 2) the expression of MAPs is different, with MAP2 mostly found in dendrites and MAP1B and tau mainly present in axons [9]. Hence, it is possible to identify the type of cytoplasmatic extension based on the specific organization of the MTs present in each one. ROLES OF CLASSICAL MAPS IN NEURITE/AXON EXTENSION Classical or structural MAPs bind along MTs and stabilize them [10]. Tau and microtubule-associated protein 1B (MAP1B) are classical MAPs, mostly present in neurons [10]. MAP1B is the first MAP expressed, with highest expression levels during axon extension [11, 12]. Downregulation of MAP1B levels in the neonatal brain coincides with the completion of axonal extension and the initiation of active synaptogenesis [13]. This reduction in MAP1B protein levels is the consequence of a gradual decrease of MAP1B mRNA levels by the end of axonogenesis [14]. This process is regulated by the fragile X mental retarda-
tion protein (FMRP), which interacts with MAP1B mRNA and regulates its translation [14]. Contrary to MAP1B, tau expression levels and molecular complexity reach a peak upon synaptic formation and neuronal maturation [15–21]. Curiously, tau is a RNA binding protein but nothing is known about the regulation of tau mRNA translation in relation with its axonal expression. Both MAP1B and tau are direct MT regulators that promote MT nucleation, polymerization, and stabilization, in vitro and in vivo, but tau is a more potent MT stabilizer than MAP1B and induces MT bundling [22–25]. Both MAPs regulate also MT dynamics [26–29]. In cells, MAP1B is present both in cytosol and bound to dynamic MTs whereas tau mostly localizes along MTs, stabilizing them [22, 27]. In non-neuronal cells, ectopic expression of MAP1B enhances the population of dynamic MTs while tau overexpression induces extension of neuritelike protrusions and MT stabilization through the formation of bundles [16, 27]. In developing neurons, MAP1B and tau mainly localize in growing axons, particularly at their distal region [30, 31]. In line with their localization, both MAP1B and tau play important roles during neurite and axon extension. Downregulation of MAP1B or tau in neuron-like cells or primary neurons, using antisense oligos or by siRNA-mediated knockdown, leads to a delay in neurite/axon extension [32–36]. Hippocampal neurons from Map1b hypomorphous or TAU knockout mice present shorter axons than wildtype neurons [33, 37]. However, while tau-deficient mice are viable and do not present noticeable alterations in brain structure or behavioral deficits until they age [37–40], MAP1B-deficient mice show more dramatic phenotypes due to abnormal brain development that range from mild to severe (lyssencephaly-like), depending on the mice genetic background [41–44]. Mice deficient in both MAP1B and tau present more severe phenotypes related to brain development than tau-deficient mice [45].
ROLES OF EBS IN NEURITE/AXON EXTENSION MT plus-end tracking proteins (+TIPs) specifically accumulate at the plus-ends of growing MTs [46, 47]. +TIPs act as local regulators of MT dynamics and influence different dynamic instability parameters [46, 47]. +TIPs also provide a link between MT distal ends and actin, cell cortex, or organelles [46, 47].
´ C.L. Sayas and J. Avila / Crosstalk between Axonal Classical Microtubule-Associated Proteins
+TIPs are ubiquitous proteins, highly conserved among eukaryotes. +TIPs comprise a group of structurally unrelated proteins that range from motor proteins to MT polymerases/depolymerases, adaptor or regulatory proteins [46, 47]. Diverse +TIPs have been shown to play important roles during different stages of neuronal development such as migration, axon extension and guidance, dendritic spine formation, and maintenance of proper communication between neurons [48]. We will focus on the known roles of the family of EB proteins during neurite and axon extension. The EB protein family consists of three members (EB1-3) and is considered as the ‘core’ +TIP family [47], since EB1/3 track MT ends autonomously and mark all growing MTs [49–54]. Every known+TIP interacts with EB1/3 and many of them require EB1like proteins for plus-end tracking. Furthermore, many +TIPs interact with each other at MT plus-ends [47]. During neuronal development, EB1/3 are present in all neuronal compartments, indicating the existence of local MT polymerization throughout the neuron [8]. In differentiating neuroblastoma cells, EB1 regulates MT growth rate, growth distance, and duration and EB1 downregulation leads to reduction in neurite length [55]. Of the three family members, EB3 is predominantly expressed in brain, in particular in neurons [56]. EB3 is localized at the plus-ends of MTs that enter filopodia in advancing growth cones where it interacts with the F-actin-binding protein drebrin [57]. This interaction is crucial for the proper formation of growth cones and neurite extension. Of note, EB3 has also been found at growing ends of dynamic MTs that enter dendritic spines [58]. In spines, EB3 modulates actin dynamics through its interaction with p140Cap, a protein that binds the F-actin binding protein cortactin [58]. EB3 might act therefore as a linker between MTs and F-actin in neurons. In adult neurons, both EB1 and EB3 have been shown to be concentrated and stabilized in the axon initial segment (AIS), where they interact directly with the scaffold protein ankyrin G (ankG) [59]. EBs coordinate a molecular and functional interplay between MTs and ankG in the AIS [59]. Furthermore, EB1 is crucial for axonal targeting of potassium channel Kv1 (also enriched in the AIS), which regulate action potential propagation, an evolutionarily conserved function important for the control of motor behavior [60]. Therefore, EBs (EB1/3) function as local regulators of MT dynamics during neurite and axon outgrowth and play central roles in the maintenance of neuronal polarity through their actions on the AIS.
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FUNCTIONAL INTERPLAY BETWEEN AXONAL MAPS AND EBS DURING AXON OUTGROWTH MTs in neurites and axons are bundled into fascicles by the cross-linking action of MAPs, and on entering the growth cone they splay out with their plus-ends oriented distally [9]. EB1/3 accumulate at MT plusends in a comet-like pattern, in contrast with classical MAPs that bind along the MT lattice [47] (Fig. 1). The number of binding sites for EBs is higher at the very tip of MT distal ends and decays at a constant rate, leading to the typical comet-shape [47]. EBs undergo a fast exchange on/off MT growing ends [61]. Therefore, a pool of EB proteins exists in the cytosol and its interaction with MTs is susceptible to regulation. Our recent findings indicate that classical MAPs regulate EB1/3 localization and function during neurite and axon extension [1]. We showed that MAP1B overexpression displaces EBs from MT plus-ends whereas MAP1B downregulation enhances EB1/3 interaction with MTs [1]. In MAP1B-deficient neurons, the behavior of EB proteins is altered, leading to changes in MT dynamics [1]. This gives rise to MT overstabilization and looping in growth cones and contributes to growth cone remodeling and a delay in axon outgrowth in Map1b-/- neurons [1]. The effect of MAP1B on EB proteins is direct; MAP1B interacts with EB1/3 and sequesters them in the cytosol of elongating neurites/axons and growth cones of developing neuronal cells (Fig. 1a, b). In this way, MAP1B reduces the effective pool of cytosolic EBs that is available to interact with MT plus-ends and keeps MT highly dynamic during neurite/axon outgrowth. Of note, while EB1 levels remains constant, expression levels of tau and EB3 increase as neurons become mature and establish synaptic contacts [17, 58]. Our data indicate that tau exerts a different type of crosstalk with EB proteins in extending neurites/axons of differentiating neuronal cells (Sayas et al, unpublished data; Fig. 1a). In line with this, MAP2, another classical neuronal (dendritic) MAP that shares with tau conserved MT-binding repeats and an amino-terminal projection domain [62], has been shown to modulate the localization of EB3 [63]. MAP2 induces EB3 redistribution to MT bundles in a prolonged response to NMDA in dendrites of mature neurons [63]. From these studies, EBs emerge as key effectors of the actions of classical MAPs during axon extension. Thus, MAP1B and tau may act as local regulators of MT dynamics by modulating the localization and
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play between tau and EBs may still occur in adult neurons. In this context, it would be interesting to study whether hyperphosphorylated tau regulates the binding of EBs to MTs. If this is the case, the abnormal localization of tau in AD or tauopathies might lead to mislocalization of EB1/3 proteins in affected brains. Given that EBs are the main known regulators of MT dynamics [65], dysregulation of EBs distribution and function could further alter MT organization under pathological situations. As a consequence, many known EBs-interacting partners might also be mislocalized in AD or tauopathies. Misdistribution of the whole set of +TIPs, which normally form protein hubs at MT plus-ends, might have extra deleterious effects on MT architecture, and subsequently, on MT-dependent axonal transport. Research should be done to confirm whether a disruption of the crosstalk between tau and EBs occurs upon neurodegeneration and how it contributes to the pathology. CONCLUSIONS
Fig. 1. Interplay between axonal MAPs and +TIPs during neuronal development. In the axon shaft (a) and growth cone (b), MAP1B localizes along MTs and in the cytosol. MAP1B interacts directly with EB1/3 and sequesters them in the cytosol of extending axons and growth cones (a and b). Moreover, microtubular MAP1B displaces EB1/3 from the MT lattice. In this way, MAP1B contributes to keep MTs highly dynamic during neuronal differentiation. On the other hand, tau, which binds MTs and induces their bundling and stabilization (detail in a), crosstalks with EB1/3, regulating MT dynamics and stability during neuronal development.
function of EB1/3. Notably, MAP1B and tau regulate EBs in different manners indicating that their roles during axon extension are not overlapping, contrary to the general view.
The correct formation and proper function of the nervous system relies on the ability of neurons to polarize and undergo major morphological changes. Rearrangements of MT cytoskeleton underlie these changes in cell shape. MT assembly and dynamics are regulated by a plethora of proteins, such as classical MAPs and +TIPs [10, 46, 47, 64]. Recent findings indicate that axon extension is regulated by the coordinated actions of axonal MAPs (MAP1B and tau) and the core + TIPs (EBs) ([1], Sayas et al., unpublished data). From these studies MAPs have emerged as direct regulators of EBs localization and function during neurite and axon outgrowth. It remains to be elucidated whether the interplay between classical MAPs and EBs, or its disruption, contributes to neurodegeneration in disorders such as AD.
POSSIBLE IMPLICATIONS IN ALZHEIMER’S DISEASE
ACKNOWLEDGMENTS
Neurofibrillary tangles, a histopathological hallmark of AD, are composed of paired helical filaments made of hyperphosphorylated tau [20]. Abnormal tau hyperphosphorylation is also a hallmark of tauopathies, other related neurodegenerative disorders [64]. Since tau modulates the interaction of EBs with MTs during neuronal development (Sayas et al., unpublished data) and their levels remain high in adult neurons [17, 58], it is likely that the inter-
C.L. Sayas was supported by CSIC and CIBERNED (Madrid), and is currently supported by the IMBRAIN project. The authors would like to acknowledge the IMBRAIN project (FP7-REGPOT-2012-CT201231637-IMBRAIN), funded under the 7th Framework Programme (Capacities). This work was supported by grants from the Spanish Research Council (CSIC) (Plan Nacional), CIBERNED and Comunidad de Madrid (Spain).
´ C.L. Sayas and J. Avila / Crosstalk between Axonal Classical Microtubule-Associated Proteins
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2080).
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