The microtubule cytoskeleton and the development of neuronal polarity

doi:10.1016/0197-4580(94)00164-V

Neurobiology of Aging

Volume 16, Issue 3, May–June 1995, Pages 229-237

https://doi.org/10.1016/0197-4580(94)00164-V Get rights and content

Abstract

The concept that axons and dendrites represent a fundamental polarization of the nerve cell has been borne out by numerous morphological, functional, and molecular studies. How does polarity arise during development? We and others have focused on the role of the microtubule cytoskeleton because microtubules (a) are essential components of axons and dendrites; (b) possess an inherent polarity at the molecular level; (c) are regulated by interactions with microtubule associated proteins (MAPS), some of which have polarized distributions in mature neurons. Here we review data on the initial acquisition of polarity as observed in neuronal culture and roles for microtubules and MAPs in this morphogenetic event. We present data clarifying some previously conflicting results on tau localization during the establishment of polarity and provide new evidence that phosphorylation of tau is spatially regulated during the development of polarity in culture. Elucidation of mechanisms locally regulating tau phosphorylation during normal neuronal development may provide clues to the significance of its abnormal phosphorylation in Alzheimer's disease.

References (54)

F.J. Ahmad et al.
Inhibition of microtubule nucleation at the neuronal centrosome compromises axon growth
Neuron
(1994)
J.P. Brion et al.
Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing and adult rat cerebellum
Neuroscience
(1988)
P.R. Burton
Dendrites of mitral cell neurons contain microtubules of opposite polarity
Brain Res.
(1988)
A. Caceres et al.
MAP2 is localized to the dendrites of hippocampal neurons which develop in culture
Brain Res
(1984)
C.G. Dotti et al.
The expression and distribution of the microtubule-associated proteins tau and microtubule-associated protein 2 in hippocampal neurons in the rat in situ and in cell culture
Neuroscience
(1987)
A. Ferreira et al.
An immunocytochemical analysis of the ontogeny of the microtubule-associated proteins MAP-2 and Tau in the nervous system of the rat
Brain Res
(1987)
A. Ferreira et al.
Microtubule formation and neurite growth in cerebellar macroneurons which develop in vitro: Evidence for the involvement of the microtubule-associated proteins, MAP-la, HMW-MAP2 and Tau
Brain Res Dev Brain Res
(1989)
A. Ferreira et al.
The expression of acetylated microtubules during axonal and dendritic growth in cerebellar macroneurons which develop in vitro
Brain Res. Dev. Brain Res.
(1989)
M. Goedert et al.
Molecular characterization of microtubule-associated proteins tau and MAP2
Trends Neurosci
(1991)
M. Goedert et al.
Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms
Neuron
(1992)

S.G. Greenberg et al.

Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau

J. Biol. Chem.

(1992)

N. Hirokawa

Microtubule organization and dynamics dependent on microtubule-associated proteins

Curr. Opin. Cell Biol.

(1994.)

M.P. Mattson

Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca²⁺ influx in cultured hippocampal neurons

Neuron

(1990)

M.P. Mattson et al.

Localized calcium influx orients axon formation in embryonic hippocampal pyramidal neurons

Brain Res. Dev. Brain Res.

(1990)

A. Matus

Microtubule-associated proteins

Curr. Opin. Cell Biol.

(1990)

B.M. Riederer et al.

Differential distribution of tau proteins in developing cat cerebellum

Brain Res. Bull.

(1994)

R. Sato-Yoshitake et al.

Microtubule-associated protein 1B: Molecular structure, localization, and phosphorylation-dependent expression in developing neurons

Neuron

(1989)

P.W. Baas et al.

The plus ends of stable microtubules are the exclusive nucleating structures for microtubules in the axon

J. Cell Biol.

(1992)

P.W. Baas et al.

Changes in microtubule polarity orientation during the development of hippocampal neurons in culture

J. Cell Biol.

(1989)

P.W. Baas et al.

Polarity orientation of microtubules in hippocampal neurons: Uniformity in the axon and nonuniformity in the dendrite

P.W. Baas et al.

Gamma-tubulin distribution in the neuron: Implications for the origins of neuritic microtubules

J. Cell Biol.

(1992)

L.I. Binder et al.

The distribution of tau in the mammalian central nervous system

J. Cell Biol.

(1985)

M.M. Black et al.

Microtubule-associated protein lb (MAPIb) is concentrated in the distal region of growing axons

J. Neurosci.

(1994)

P.A. Brittis et al.

Cell adhesion molecules in concert with repulsive molecules govern intraretinal axon guidance: A time lapse study of the living retina

Soc. Neuroscience Abstr.

(1993)

R.D. Burgoyne

High molecular weight microtubule-associated proteins of brain

A. Caceres et al.

Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons

Nature

(1990)

A. Caceres et al.

The effect of tau antisense oligonucleotides on neurite formation of cultured cerebellar macroneurons

J. Neurosci.

(1991)

Cited by (57)

To target Tau pathologies, we must embrace and reconstruct their complexities
2021, Neurobiology of Disease
Citation Excerpt :
In neuronal cells, under normal conditions, Tau is predominantly localized to axonal compartment (Kosik and Finch, 1987) and is involved in axonal (Zempel and Mandelkow, 2019) and synaptic functions (Hoover et al., 2010; Decker and Mandelkow, 2019) as well as in neurovascular coupling processes (Park et al., 2020). By virtue of its microtubule (MT)-binding profile, Tau was found to carry out important roles in cytoskeletal maintenance (Mandell and Banker, 1995), mitochondrial transport (Shahpasand et al., 2012), trafficking of cargo along MTs (Chaudhary et al., 2018), cell signalling (Li et al., 2018), and maintenance of chromatin organization (Villasante et al., 1981; Galas et al., 2019). Tau is also involved in many cellular processes and pathways, such as stress responses (Maina et al., 2018) and cell proliferation (Yi et al., 2019).
The accumulation of hyperphosphorylated fibrillar Tau aggregates in the brain is one of the defining hallmarks of Tauopathy diseases, including Alzheimer's disease. However, the primary events or molecules responsible for initiation of the pathological Tau aggregation and spreading remain unknown. The discovery of heparin as an effective inducer of Tau aggregation in vitro was instrumental to enabling different lines of research into the role of Tau aggregation in the pathogenesis of Tauopathies. However, recent proteomics and cryogenic electron microscopy (cryo-EM) studies have revealed that heparin-induced Tau fibrils generated in vitro do not reproduce the biochemical and ultrastructural properties of disease-associated brain-derived Tau fibrils. These observations demand that we reassess our current approaches for investigating the mechanisms underpinning Tau aggregation and pathology formation. Our review article presents an up-to-date survey and analyses of 1) the evolution of our understanding of the interactions between Tau and heparin, 2) the various structural and mechanistic models of the heparin-induced Tau aggregation, 3) the similarities and differences between brain-derived and heparin-induced Tau fibrils; and 4) emerging concepts on the biochemical and structural determinants underpinning Tau pathological heterogeneity in Tauopathies. Our analyses identify specific knowledge gaps and call for 1) embracing the complexities of Tau pathologies; 2) reassessment of current approaches to investigate, model and reproduce pathological Tau aggregation as it occurs in the brain; 3) more research towards a better understanding of the naturally-occurring cofactor molecules that are associated with Tau brain pathology initiation and propagation; and 4) developing improved approaches for in vitro production of the Tau aggregates and fibrils that recapitulate and/or amplify the biochemical and structural complexity and diversity of pathological Tau in Tauopathies. This will result in better and more relevant tools, assays, and mechanistic models, which could significantly improve translational research and the development of drugs and antibodies that have higher chances for success in the clinic.
Lost after translation: Missorting of Tau protein and consequences for Alzheimer disease
2014, Trends in Neurosciences
Citation Excerpt :
Although most protein synthesis in mature mammalian neurons occurs in the soma, the axon represents up to 99% of the volume of a cell, requiring efficient transport. The process of neuritic outgrowth and cell differentiation can be subdivided into five ‘Banker’ stages [16,30]: (i) formation of lamellipodia; (ii) outgrowth of minor processes; (iii) formation and growth of the axon; (iv) growth of the dendrites; and (iv) maturation. With increasing maturation, Tau becomes sorted into axons (in contrast to MAP2 which is restricted to soma and dendrites).
Tau is a microtubule-associated-protein that is sorted into neuronal axons in physiological conditions. In Alzheimer disease (AD) and other tauopathies, Tau sorting mechanisms fail and Tau becomes missorted into the somatodendritic compartment. In AD, aberrant amyloid-β (Aβ) production might trigger Tau missorting. The physiological axonal sorting of Tau depends on the developmental stage of the neuron, the phosphorylation state of Tau and the microtubule cytoskeleton. Disease-associated missorting of Tau is connected to increased phosphorylation and aggregation of Tau, and impaired microtubule interactions. Disease-causing mechanisms involve impaired transport, aberrant kinase activation, non-physiological interactions of Tau, and prion-like spreading. In this review we focus on the physiological and pathological (mis)sorting of Tau, the underlying mechanisms, and effects in disease.
Acrylamide alters neurotransmitter induced calcium responses in murine ESC-derived and primary neurons
2014, NeuroToxicology
Citation Excerpt :
Moreover, we found neurites with strong Tau and weak MAP2 signals in ESCN. In mature neurons MAP2 is absent in axons and located only somato-dendritically, whereas Tau is mainly present in axons (Bernhardt and Matus, 1984; Binder et al., 1985; Dotti et al., 1987; Kosik and Finch, 1987; Mandell and Banker, 1995). In the developing neuron, Tau segregates into axons and MAP2 into dendrites right after axogenesis (Matus, 1990).
Stem cell-derived specialized cell types are of interest as an alternative cell system to identify and research neurotoxic effects and modes of action. Developmental toxicity may be studied during differentiation, while organ-specific toxicity may be assessed in fully functional cells, such as neurons. In this study we tested if fully differentiated neurons derived from murine embryonic stem cells (ESCN) could be used to investigate the effects of the well characterized neurotoxic model compound acrylamide (ACR) and if ESCN behave similar to murine primary cortical neurons (pCN) from 16 days old embryos. We characterized the differentiation process of cryopreserved ESC-derived neural precursor cells (NPC) differentiating to ESCN. During the differentiation process (days 11–20) a strong increase in calcium responses to glutamate, acetylcholine and GABA were observed. Moreover, neuron specific marker proteins, β-III-tubulin, MAP2, Tau, Rbfox3 and synaptophysin showed similar patterns to pCN. In ESCN and pCN the neuronal structure, e.g. neurites, was not affected by low concentrations of ACR [0.5–1.6 mM]. However, 24 h incubation periods with 0.5–1.6 mM ACR led to a reduction of acetylcholine and glutamate induced calcium responses. In conclusion, we show that non-cytotoxic concentrations of ACR alter neurotransmission in ESCN as well as pCN.
The Cytoskeleton of Neurons and Glia
2012, Basic Neurochemistry
The aim of this chapter is twofold: first, to provide an introduction to the cytoskeletal elements themselves and second, to examine their role in neuronal and glial function. Throughout, the emphasis has been given on the cytoskeleton that is mentioned as a vital, dynamic component of the nervous system. Neurons and glia exhibit a remarkable diversity of shapes. These different morphologies are so characteristic and distinctive that they have been used since the time of Cajal to define neural functions. For example, Purkinje cells in the cerebellum have such distinctive morphologies that they are readily identifiable in any vertebrate. Neurons do not divide, so their distinctive morphologies are maintained throughout life. Biochemical and immunological markers are used to delineate neuronal populations. A brief description related to the establishment of cytoskeletal elements within axons and dendrites are also given in the chapter that illustrates the dynamic nature of the cytoskeleton. The sequence of events has been described for neurons in primary culture.
The Cytoskeleton of Neurons and Glia
2011, Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology: Eighth Edition
The aim of this chapter is twofold: first, to provide an introduction to the cytoskeletal elements themselves and second, to examine their role in neuronal and glial function. Throughout, the emphasis has been given on the cytoskeleton that is mentioned as a vital, dynamic component of the nervous system. Neurons and glia exhibit a remarkable diversity of shapes. These different morphologies are so characteristic and distinctive that they have been used since the time of Cajal to define neural functions. For example, Purkinje cells in the cerebellum have such distinctive morphologies that they are readily identifiable in any vertebrate. Neurons do not divide, so their distinctive morphologies are maintained throughout life. Biochemical and immunological markers are used to delineate neuronal populations. A brief description related to the establishment of cytoskeletal elements within axons and dendrites are also given in the chapter that illustrates the dynamic nature of the cytoskeleton. The sequence of events has been described for neurons in primary culture.
The development of neuronal morphology in insects
2005, Current Biology
Citation Excerpt :
Neurons develop intricate and astoundingly diverse branching morphologies. In both vertebrate and invertebrate neurons, axons appear to emerge first from the cell body, followed by the growth of dendrites [8,31,32]. A major difference in morphology between invertebrate and vertebrate neurons is that the majority of vertebrate neurons is multipolar while the majority of invertebrate neurons is unipolar [33,34].
Neurons are highly polarized cells with some regions specified for information input — typically the dendrites— and others specialized for information output — the axons. By extending to a specific location and branching in a specific manner, the processes of neurons determine at a fundamental level how the nervous system is wired to produce behavior. Recent studies suggest that relatively small changes in neuronal morphology could conceivably contribute to striking behavioral distinctions between invertebrate species. We review recent data that begin to shed light on how neurons extend dendrites to their targets and acquire their particular branching morphologies, drawing primarily on data from genetic model organisms. We speculate about how and why the actions of these genes might facilitate the diversification of dendritic morphology.

View all citing articles on Scopus

View full text

The microtubule cytoskeleton and the development of neuronal polarity

Abstract

Neuron

Neuroscience

Brain Res.

Brain Res

Neuroscience

Brain Res

Brain Res Dev Brain Res

Brain Res. Dev. Brain Res.

Trends Neurosci

Neuron

J. Biol. Chem.

Curr. Opin. Cell Biol.

Neuron

Brain Res. Dev. Brain Res.

Curr. Opin. Cell Biol.

Brain Res. Bull.

Neuron

The plus ends of stable microtubules are the exclusive nucleating structures for microtubules in the axon

J. Cell Biol.

Changes in microtubule polarity orientation during the development of hippocampal neurons in culture

J. Cell Biol.

Polarity orientation of microtubules in hippocampal neurons: Uniformity in the axon and nonuniformity in the dendrite

Gamma-tubulin distribution in the neuron: Implications for the origins of neuritic microtubules

J. Cell Biol.

The distribution of tau in the mammalian central nervous system

J. Cell Biol.

Microtubule-associated protein lb (MAPIb) is concentrated in the distal region of growing axons

J. Neurosci.

Cell adhesion molecules in concert with repulsive molecules govern intraretinal axon guidance: A time lapse study of the living retina

Soc. Neuroscience Abstr.

High molecular weight microtubule-associated proteins of brain

Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons

Nature

The effect of tau antisense oligonucleotides on neurite formation of cultured cerebellar macroneurons

J. Neurosci.