We need axon growth to connect regions up thru the white matter. What is your doctor's rehab protocol to do just that?
A new view of axon growth and guidance grounded in the stochastic dynamics of
actin networks
Rameen Forghani 1
, Aravind Chandrasekaran 1,2,3,†, Garegin Papoian 2,3 and
Edward Giniger1
1National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
2Department of Chemistry and Biochemistry, and 3Institute for Physical Science and Technology, University of
Maryland, College Park, MD 20742-3281, USA
GP, 0000-0001-8580-3790; EG, 0000-0002-8340-6158
The mechanism of axon growth and guidance is a core, unsolved problem in
neuroscience and cell biology. For nearly three decades, our view of this pro-
cess has largely been based on deterministic models of motility derived from
studies of neurons cultured in vitro on rigid substrates. Here, we suggest a fun-
damentally different, inherently probabilistic model of axon growth, one that
is grounded in the stochastic dynamics of actin networks. This perspective is
motivated and supported by a synthesis of results from live imaging of a
specific axon growing in its native tissue in vivo, together with single-molecule
computational simulations of actin dynamics. In particular, we show how
axon growth arises from a small spatial bias in the intrinsic fluctuations of
the axonal actin cytoskeleton, one that produces net translocation of the
axonal actin network by differentially modulating local probabilities of net-
work expansion versus compaction. We discuss the relationship between
this model and current views of axon growth and guidance mechanism and
demonstrate how it offers explanations for various longstanding puzzles in
this field. We further point out the implications of the probabilistic nature
of actin dynamics for many other processes of cell morphology and motility.
1. Introduction
At the single-cell level, biology is statistical. Macroscopic features of organisms,
such as their morphology and physiology, tend to be remarkably consistent and
predictable, but the cellular and subcellular machines that make those features
show tremendous fluctuation and variability in their moment-to-moment
activity [1–5]. One of the great challenges in contemporary cell biology is to
understand the mechanisms by which noisy biochemistry and biophysics
give rise to reliable biological outcomes.
In this Commentary, we will consider the implications of this challenge for
the mechanism of axon growth and guidance in the developing nervous system.
The function of a nervous system depends on its pattern of wiring, where the
‘wire’ that carries information from one neuron to those downstream in its
neural circuit is called an axon. However, those wires do not start out having
their complex final shapes, they have to grow [6]. Each starts as a little stub,
a neurite, on the cell body of its neuron and that stub has to extend, growing
along a specific trajectory until the axon reaches its appropriate target site,
sometimes far away at the end of a tortuous path. To find out how the axon
grows, we have to look into the machinery at the tip of the axon that drives
its extension and allows it to follow its particular path. The heart of this
growth machinery are two structural proteins, actin, which polymerizes into
filaments to form a dynamic meshwork that generates shape and force, and
tubulin, which forms a second kind of structural element, the microtubules, that cooperate with actin to build the axon. The challenge,
then, is to understand how the organization and dynamics
of actin and microtubules change in response to the local
tissue environment to produce guided axon growth. This pro-
blem of how axons grow has long been recognized to be one
of the central mysteries in neuroscience [7]. Many excellent
reviews provide a detailed picture of the different hypotheses
that have been offered to account for the mechanism of axon
growth and guidance [8–12]. Despite extensive study, how-
ever, it has been extremely difficult to integrate these
differing ideas into a unified understanding of axon growth
and even more so to apply those hypotheses to specific
axon patterning decisions that one observes in vivo.
Here, we will approach this same fundamental problem, but
in a different way. Rather than trying to provide an encyclopae-
dic overview of investigations into the mechanism of axon
growth and guidance, we will restrict our focus to analyse a
single, specific axon developing in its native tissue, an axon,
moreover, for which the underlying dynamics have been quanti-
fied in detail in vivo at multiple levels of resolution. After
reviewing some of the key data, we will discuss how the obser-
vations of this axon, called TSM1 (twin sensillae of the margin 1),
suggest a new and unexpected model for the mechanism of axon
growth and guidance. In brief, we will see how the stochastic
fluctuations of individual actin filaments produce dynamic redis-
tribution of the global actin network in the axon at a multi-
micrometre scale and how this in turn produces directed axon
growth. To come to that endpoint, we will start by examining
the large features of the TSM1 axon and work our way down
to the small ones, start with a description of the morphology
and actin distribution of this axon in vivo, then focus down on
biochemical processes that produce that cell biology, and then
focus further on the single-molecule biophysics that underpin
the entire mechanism. We then synthesize these findings in a
coherent model for the mechanism of growth of TSM1. Finally,
we show how this model uncovers an underlying simplicity
that may reconcile some of the divergent views in the field of
axon growth and explain some longstanding mysteries. In the
body of this Commentary, we will focus our attention exclusively
on the dynamics of the actin cytoskeleton. At the end, however,
we will briefly extend our discussion to consider some of the
ways that the microtubule cytoskeleton may fit into the story
to modulate the actin-based processes that are presented here
in more detail [13–15]. It should be kept in mind that throughout
this Commentary, we will be presenting our own view of current
ideas in the field and the challenges presented by recent in vivo
experiments. Other investigators will unquestionably view each
of these somewhat differently than we do. Our goal, however,
is to stimulate discussion and further experiments. If we achieve
that effect, then this paper will have fulfilled its purpose. Before
we begin, however, we must first give a deeper introduction to
the nature of an axon and the events that occur at its growing tip.
, Aravind Chandrasekaran 1,2,3,†, Garegin Papoian 2,3 and
Edward Giniger1
1National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
2Department of Chemistry and Biochemistry, and 3Institute for Physical Science and Technology, University of
Maryland, College Park, MD 20742-3281, USA
GP, 0000-0001-8580-3790; EG, 0000-0002-8340-6158
The mechanism of axon growth and guidance is a core, unsolved problem in
neuroscience and cell biology. For nearly three decades, our view of this pro-
cess has largely been based on deterministic models of motility derived from
studies of neurons cultured in vitro on rigid substrates. Here, we suggest a fun-
damentally different, inherently probabilistic model of axon growth, one that
is grounded in the stochastic dynamics of actin networks. This perspective is
motivated and supported by a synthesis of results from live imaging of a
specific axon growing in its native tissue in vivo, together with single-molecule
computational simulations of actin dynamics. In particular, we show how
axon growth arises from a small spatial bias in the intrinsic fluctuations of
the axonal actin cytoskeleton, one that produces net translocation of the
axonal actin network by differentially modulating local probabilities of net-
work expansion versus compaction. We discuss the relationship between
this model and current views of axon growth and guidance mechanism and
demonstrate how it offers explanations for various longstanding puzzles in
this field. We further point out the implications of the probabilistic nature
of actin dynamics for many other processes of cell morphology and motility.
1. Introduction
At the single-cell level, biology is statistical. Macroscopic features of organisms,
such as their morphology and physiology, tend to be remarkably consistent and
predictable, but the cellular and subcellular machines that make those features
show tremendous fluctuation and variability in their moment-to-moment
activity [1–5]. One of the great challenges in contemporary cell biology is to
understand the mechanisms by which noisy biochemistry and biophysics
give rise to reliable biological outcomes.
In this Commentary, we will consider the implications of this challenge for
the mechanism of axon growth and guidance in the developing nervous system.
The function of a nervous system depends on its pattern of wiring, where the
‘wire’ that carries information from one neuron to those downstream in its
neural circuit is called an axon. However, those wires do not start out having
their complex final shapes, they have to grow [6]. Each starts as a little stub,
a neurite, on the cell body of its neuron and that stub has to extend, growing
along a specific trajectory until the axon reaches its appropriate target site,
sometimes far away at the end of a tortuous path. To find out how the axon
grows, we have to look into the machinery at the tip of the axon that drives
its extension and allows it to follow its particular path. The heart of this
growth machinery are two structural proteins, actin, which polymerizes into
filaments to form a dynamic meshwork that generates shape and force, and
tubulin, which forms a second kind of structural element, the microtubules, that cooperate with actin to build the axon. The challenge,
then, is to understand how the organization and dynamics
of actin and microtubules change in response to the local
tissue environment to produce guided axon growth. This pro-
blem of how axons grow has long been recognized to be one
of the central mysteries in neuroscience [7]. Many excellent
reviews provide a detailed picture of the different hypotheses
that have been offered to account for the mechanism of axon
growth and guidance [8–12]. Despite extensive study, how-
ever, it has been extremely difficult to integrate these
differing ideas into a unified understanding of axon growth
and even more so to apply those hypotheses to specific
axon patterning decisions that one observes in vivo.
Here, we will approach this same fundamental problem, but
in a different way. Rather than trying to provide an encyclopae-
dic overview of investigations into the mechanism of axon
growth and guidance, we will restrict our focus to analyse a
single, specific axon developing in its native tissue, an axon,
moreover, for which the underlying dynamics have been quanti-
fied in detail in vivo at multiple levels of resolution. After
reviewing some of the key data, we will discuss how the obser-
vations of this axon, called TSM1 (twin sensillae of the margin 1),
suggest a new and unexpected model for the mechanism of axon
growth and guidance. In brief, we will see how the stochastic
fluctuations of individual actin filaments produce dynamic redis-
tribution of the global actin network in the axon at a multi-
micrometre scale and how this in turn produces directed axon
growth. To come to that endpoint, we will start by examining
the large features of the TSM1 axon and work our way down
to the small ones, start with a description of the morphology
and actin distribution of this axon in vivo, then focus down on
biochemical processes that produce that cell biology, and then
focus further on the single-molecule biophysics that underpin
the entire mechanism. We then synthesize these findings in a
coherent model for the mechanism of growth of TSM1. Finally,
we show how this model uncovers an underlying simplicity
that may reconcile some of the divergent views in the field of
axon growth and explain some longstanding mysteries. In the
body of this Commentary, we will focus our attention exclusively
on the dynamics of the actin cytoskeleton. At the end, however,
we will briefly extend our discussion to consider some of the
ways that the microtubule cytoskeleton may fit into the story
to modulate the actin-based processes that are presented here
in more detail [13–15]. It should be kept in mind that throughout
this Commentary, we will be presenting our own view of current
ideas in the field and the challenges presented by recent in vivo
experiments. Other investigators will unquestionably view each
of these somewhat differently than we do. Our goal, however,
is to stimulate discussion and further experiments. If we achieve
that effect, then this paper will have fulfilled its purpose. Before
we begin, however, we must first give a deeper introduction to
the nature of an axon and the events that occur at its growing tip.
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