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10 September 2011
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Further
Regulation of Terminal
Differentiation Programs
in the Nervous System
Oliver Hobert
Howard Hughes Medical Institute and Department of Biochemistry and Molecular
Biophysics, Columbia University Medical Center, New York, NY 10032;
email: or38@columbia.edu
Keywords
neuronal identity, transcriptional regulation, terminal selector,
regulon
Abstract
The generation of individual neuron types in the nervous system is a
multistep process whose endpoint is the expression of neuron type
specic batteries of terminal differentiation genes that determine the
functional properties of a neuron. This review focuses on the regulatory mechanisms that are involved in controlling the terminally differentiated state of a neuron. I review several case studies from invertebrate and vertebrate nervous systems that reveal that many terminal
differentiation features of a neuron are coregulated via terminal selector
transcription factors that initiate and maintain terminal differentiation
programs.
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Contents
INTRODUCTION . . . . . . . . . . . . . . . . . .
COREGULATION OF TERMINAL
DIFFERENTIATION GENES
THROUGH TERMINAL
SELECTORS . . . . . . . . . . . . . . . . . . . . .
Coregulation of Neuronal Terminal
Differentiation Batteries in
Caenorhabditis elegans . . . . . . . . . . . .
Terminal Selector Transcription
Factors Coregulate Terminal
Differentiation Batteries . . . . . . . . .
Coregulation and Terminal
Selectors in Vertebrates . . . . . . . . .
MAINTENANCE OF THE
DIFFERENTIATED STATE . . . . .
PARALLEL REGULATORY
ROUTINES . . . . . . . . . . . . . . . . . . . . . .
COMBINATORIAL CODES OF
TERMINAL SELECTOR
FUNCTION . . . . . . . . . . . . . . . . . . . . . .
DIVERSIFICATION
DOWNSTREAM OF
TERMINAL SELECTORS . . . . . . .
COREGULATION OUTSIDE
THE NERVOUS SYSTEM . . . . . . .
THE HOURGLASS TOPOLOGY
OF REGULATORY
PROGRAMS . . . . . . . . . . . . . . . . . . . . . .
FUTURE CHALLENGES . . . . . . . . . . .
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INTRODUCTION
Terminal
differentiation genes:
effector genes that
dene the functional
properties of a mature,
nondividing neuron
throughout its life
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COREGULATION OF TERMINAL
DIFFERENTIATION GENES
THROUGH TERMINAL
SELECTORS
How to study the regulation of terminal differentiation genes? Early studies conducted in
the 1980s and 1990s attempted to dissect the
regulatory control regions of terminal differentiation genes with reporter genes expressed in
cell lines or primary cell cultures. Such studies
were hard to interpret because the complement
of regulatory factors often differs between a heterologous ex vivo context and a cell undergoing
differentiation in its normal organismal context.
The most incisive way to conduct studies on
the regulatory architecture of gene expression
programs is to carry out studies in vivo, ideally
within an animal, using transgenic approaches.
Coregulation:
regulation of a set of
distinct genes (a gene
battery) through a
similar cis-regulatory
signature
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Autoregulatory
module
Terminal
selector(s)
Single input
module (SIM)
Others
Signaling
proteins
Ion channels
Neurotransmitter
pathway
Autoreceptors
Neurotransmitter
receptors
Neurotransmitters
Figure 1
Terminal selector regulons. A terminal selector directly controls the expression of terminal differentiation genes, representative
examples of which are depicted schematically here. Direct regulation is mediated via cis-regulatory motifs (black boxes) located in
proximity to members of the terminal gene batteries. The terminal selector can be a single protein, a heterodimer of two proteins that
cooperatively bind a specic motif, or a more complex assembly of separate trans-acting factors that bind to distinct cis-regulatory
elements that together form a specic cis-regulatory signature. An example of the last is an assembly of ETS and two distinct
homeodomain-binding sites that controls expression of a terminal gene battery in Caenorhabditis elegans dopaminergic neurons
(O. Hobert et al., unpublished data).
signatures (i.e., specic combinations of distinct cis-regulatory motifs) suggests that within
a specic neuron type, each gene battery is
controlled by a common trans-acting factor or
a combination thereof (Figure 1).
Selector: any
regulatory factor that
controls the identity of
a developing region or
organ at any stage of
development
Terminal selector: a
transcription factor (or
a combination of
several) that directly
initiates and maintains
expression of terminal
differentiation genes
Regulon: a set of
coregulated genes and
the transcription
factor(s) that directly
controls these genes
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Table 1 Examples of invertebrate and vertebrate terminal selectors and their targets. See text for references
Terminal
selector
Type of transcription
factor
Terminal neuron
identity controlled by
terminal selector
CHE-1
C. elegans gustatory
neuron class ASE
TTX-3/CEH-10
LIM/Prd homeodomains
C. elegans cholinergic
interneuron class AIY
UNC-86/MEC-3
POU/LIM
homeodomains
C. elegans glutamatergic
touch sensory neurons
UNC-30
Pitx-type homeodomain
C. elegans GABAergic
motor neurons
AST-1/CEH-43
ETS/homeodomain
C. elegans dopaminergic
neuron
UNC-3
EBF-type
C. elegans A/B-type
cholinergic motor
neurons
Pet-1
ETS domain
Mouse serotonergic
neurons
Crx
Homeodomain
Mouse retinal
photoreceptors
Nurr1/Pitx-3
C4 zinc
nger/homeodomain
Mouse midbrain
dopaminergic neurons
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Cholinergic A/B-type
motor neurons
Cholinergic AIY
interneuron
Cho
Cho
ChAT
ChAT
AcCh
CEH10
AcCh
VAChT
TTX-3
ChT
VAChT
UNC-3
ChT
A/B-type
motorneurons
UNC-3
AIY
interneurons
Other cholinergic
neurons
CEH- TTX-3
10
?
Figure 2
Terminal differentiation genes shared by distinct neuron types are controlled by distinct terminal selectors.
(a) Genes coding for proteins involved in acetylcholine (AcCh) synthesis, transport, and reuptake
(cholinergic pathway genes) are expressed in distinct neuronal cell types (example shown here: Caenorhabditis
elegans AIY interneurons and A/B-type ventral cord motor neurons) in which they are under control of
distinct terminal selectors, namely the TTX-3/CEH-10 homeodomain heterodimer in AIY (Wenick &
Hobert 2004) and the EBF-type transcription factor UNC-3 in ventral cord motor neurons (P. Kratsios &
O. Hobert, submitted). ChAT, choline acetyltransferase; Cho, choline; ChT, choline transporter; VAChT,
vesicular acetylcholine transporter. (b) The cis-regulatory regions of cholinergic pathway genes, which are
expressed in several distinct neuron types, contain a collection of distinct terminal selector binding sites.
Terminal selector motifs may occur in multiple copies, and they also may be interspersed (not shown), which
may complicate the isolation of discrete and separable elements for expression of terminal differentiation
genes in individual neuron types.
Chromatin
immunoprecipitation
(ChIP): a technique
that assesses binding of
a transcription factor
to cis-regulatory
control regions in
genomic DNA in vivo
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deployed at different stages during the differentiation process (Blackshaw et al. 2004). Both
early and late photoreceptor genes can, nevertheless, be direct targets of Crx (Corbo et al.
2010). The onset of expression of early versus
late genes might be determined by the specic
architectural features of the cis-regulatory
elements that control their expression, such as
the number and afnity of Crx sites and their
spacing and orientation relative to other adjacently bound transcription factors. Although
the rules of such cis-regulatory grammar are
not known in detail for any system, the organ
selector gene, pha-4, in C. elegans offers an
informative example. During foregut development, the afnity of the binding sites for pha-4
determines whether target genes are expressed
early or late (Gaudet & Mango 2002).
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Hobert
are terminal selectors for midbrain dopaminergic neurons (Smidt & Burbach 2009). Both
proteins are required for the expression of
many terminal differentiation genes, they are
sufcient to induce dopaminergic fate in an in
vitro differentiation model, and recent ChIP
analysis demonstrates that they bind directly to
cis-regulatory control regions of terminal differentiation targets ( Jacobs et al. 2007, 2009a,b;
Martinat et al. 2006). On the molecular level,
the mechanistic basis of the cooperation
between Nurr1 and Pitx3 lies in Nurr1 being
a transcriptional repressor through association with a corepressor protein. In midbrain
dopaminergic neurons, the only site of Pitx3 expression in the central nervous system, Pitx3 is
capable of displacing this corepressor, thereby
allowing Pitx3 and Nurr1 to jointly activate
target gene expression ( Jacobs et al. 2009b).
Etv1. The role of the C. elegans ETS domain
transcription factor ast-1 as a terminal selector of dopaminergic neurons appears to be conserved in vertebrates, as the knockout of Etv1, a
homolog of ast-1, results in the failure of olfactory bulb dopaminergic neurons to terminally
differentiate (Flames & Hobert 2009). As in
C. elegans, mouse Etv1 directly controls a key
terminal differentiation marker of dopaminergic neurons, tyrosine hydroxylase (Cave et al.
2010, Flames & Hobert 2009). However, the
differentiation defect observed in Etv1 mutant
mice does not appear to extend equally to all terminal features of olfactory bulb dopaminergic
neurons (Cave et al. 2010). This may be because
ast-1, and likely Etv1 as well, requires a specic
set of cofactors that can partially compensate for
loss of ast-1 (O. Hobert et al., unpublished data).
Other examples. Several other postmitotically expressed vertebrate transcription factors
are required for the expression of terminal features of a neuron and, consequently, have been
referred to as selector genes in the literature.
However, in all of these cases it remains to
be shown whether these transcription factors
directly control terminal differentiation genes
or whether they instead act further upstream in
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MAINTENANCE OF THE
DIFFERENTIATED STATE
One critical, key feature of invertebrate and vertebrate terminal selectors is their sustained expression throughout the life of a neuron. This
observation suggests that terminal selectors
may not only initiate the expression of terminal differentiation genes but also maintain their
expression. Conrming the sustained function
of terminal selectors, genetic approaches in
C. elegans have revealed that postembryonic
removal of a terminal selector results in the
loss of the differentiated properties of a neuron
(Etchberger et al. 2009, Flames & Hobert
2009). Similarly, removal of mouse Pet-1
in the adult nervous system through a Cre
recombinasemediated strategy results in a progressive loss of serotonergic neuron function
and loss of expression of terminal differentiation genes such as tryptophan hydroxylase (Liu
et al. 2010). A loss of dopaminergic terminal
fate markers is also observed upon removal of
Nurr1 in adult mice (Kadkhodaei et al. 2009),
further corroborating the importance of sustained terminal selector expression.
Direct transcriptional autoregulation ensures the sustained expression of terminal
selectors (Figure 1). That is, both C. elegans
terminal selectors and mouse terminal selectors
such as Pet-1 or Crx contain binding sites
for themselves in their own cis-regulatory
control regions. Mutating these binding sites
in the context of transcriptional reporters that
monitor terminal selector expression does not
affect initiation of their expression but does
affect maintenance of expression (Bertrand &
Hobert 2009). Moreover, genetic removal of
PARALLEL REGULATORY
ROUTINES
In C. elegans, the knockout of a given terminal
selector results in loss of the expression of many
terminal identity components of a neuron, but
several molecular identiers remain unaffected.
For example, sensory neurons continue to express panneuronal and pansensory features
upon removal of the che-1 gene, a terminal
selector for gustatory neuron specication
(Uchida et al. 2003), or upon removal of ast-1,
a terminal selector for dopaminergic neurons
(Flames & Hobert 2009). Similarly, loss of the
mouse terminal selector Pet-1 does not affect
the overall neuronal identity of serotonergic
neurons; rather, it affects their neuron type
specic properties (Hendricks et al. 2003).
Components of terminal neuron identity that
are not affected upon loss of these terminal
selectors may be regulated by another terminal
selector(s) acting in parallel. For example, in
C. elegans, and possibly other organisms as
well, pansensory neuron features, i.e., many
or most components of all ciliated apparatus
of all sensory neurons, are coregulated via a
common cis-regulatory motif (the X box) and
its cognate transcription factor DAF-19, a
phylogenetically conserved RFX-type factor
(Swoboda et al. 2000; Figure 3). Similarly, on
the basis of the bioinformatically determined
presence of shared cis-regulatory motifs in
many panneuronally expressed genes in invertebrates and vertebrates, several researchers
have speculated (though not experimentally
conrmed) that a coregulatory strategy may
also control panneuronal features (Hadley
et al. 2006, Liu et al. 2009, Ruvinsky et al.
2007). Taken together, several parallel-acting
regulons appear to control gene expression
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CHE-1
X1
X2
X3
X4
DAF-19
X5
X6
Neuron-type specific
identity (terminal selector)
X1
X2
X3
X4
X5
X6
Pan-sensory identity
(terminal selector)
X1
X2
X3
X4
X5
X6
Pan-neuronal identity
(?)
ASE motif
X box
N1 box
Figure 3
Multiple terminal selector regulons dene the terminal molecular signatures of a neuron. As exemplied
with the C. elegans ciliated gustatory neuron class ASE, the molecular signature of a terminally differentiated
neuron can be broken down into several distinct regulons, each controlled via a distinct, cognate terminal
selector. One is controlled by the terminal selector CHE-1, which controls ASE-specic identity features
(see Table 1 for examples) (Etchberger et al. 2007). The second regulon is controlled by the RFX-type
transcription factor DAF-19, which controls expression of the core components of the ciliated structures of
the ASE (as well as all other sensory neurons) via an X box (Swoboda et al. 2000). The third regulon is as yet
hypothetical and may be composed of a battery of coregulated panneuronal features that are unaffected by
che-1 and daf-19. Coregulation of panneuronal features is presumed to exist on the basis of bioinformatic
identication of a shared motif, the N1 box, in panneuronally expressed genes (Ruvinsky et al. 2007).
COMBINATORIAL CODES
OF TERMINAL SELECTOR
FUNCTION
Most known terminal selectors are expressed
in several distinct neuron types. In analogy to
transcription factors that act earlier in neuronal
development ( Jessell 2000), the specicity of
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their activity as terminal selectors in individual neuron types is determined by combinatorial codes of terminal selectors. For example,
the ttx-3 LIM homeobox gene is a terminal
selector for a cholinergic interneuron class in
C. elegans called AIY, but is also expressed in
several sensory neurons, where it has no apparent terminal selector function (Altun-Gultekin
et al. 2001). However, AIY neurons express another gene, the ceh-10 Prd homeobox gene,
which is itself expressed in several distinct neuron types (Altun-Gultekin et al. 2001). But
the expression of ttx-3 and ceh-10 overlaps exclusively in AIY, where the two proteins heterodimerize to cooperatively activate downstream terminal differentiation genes (Wenick
& Hobert 2004).
In vertebrates, the specicity of the more
broadly expressed terminal selector for midbrain dopaminergic neurons, Nurr1, is ensured
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HLH-2
HLH-3
REF-2 HLH-16
REF-2
bHLHs
TTX-3
TTX-3
CEH-10
Wnt
POP-1
TTX-3
ceh-10
TTX-3
AIY
interneuron
Time
Multiple, transient
regulatory inputs
AIY
motif
TTX-3
CEH-10
Battery
SMDD motor
neuron
b
ttx-3
Wnt
TTX-3
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Terminal
selector(s)
TF
CEH-10
Terminal diff.
battery
ttx-3
ceh-10
X1
X2
X3
X4
X5
TF
X6
Autoregulation
(lock in)
Figure 4
The hourglass topology of terminal selector gene function. (a) An example from C. elegans that illustrates the complex nature of the
regulatory strategy that turns on the two terminal selectors ttx-3 and ceh-10 in the AIY interneuron class (Bertrand & Hobert 2009;
V. Bertrand & O. Hobert, unpublished data). Once turned on via a multitude of transient regulatory inputs [i.e., the REF-2 and basic
helix-loop-helix (bHLH) factors are only transiently expressed; the Wnt signal is also transient], ttx-3 and ceh-10 initiate and maintain
the expression of terminal differentiation genes and ensure their own maintenance through autoregulation. All of this is achieved by a
cis-regulatory element called the AIY motif (red box) that is bound cooperatively by TTX-3 and CEH-10. Because of the lack of the
Wnt signal, ceh-10 is not turned on in the sister of the AIY interneuron, the SMDD motor neuron; thus, ttx-3 cannot maintain its own
expression, and the AIY gene battery is not expressed in SMDD. (b) Terminal selectors may be bottlenecks in an hourglass that link
complex upstream regulatory events to the coordinated expression of terminal gene batteries. In other developmental contexts, terminal
selectors have also been termed input/output genes (Stern & Orgogozo 2008). Terminal selectors are not regulatory endpoints;
however, they may regulate the expression of downstream regulatory factors to control the expression of specic subroutines that could,
e.g., diversify gene expression proles within a specic neuron class. Terminal selectors may cooperate with downstream regulators to
turn on terminal genes, thereby constituting a feed-forward motif (Alon 2007).
DIVERSIFICATION
DOWNSTREAM OF
TERMINAL SELECTORS
Even though terminal selectors directly regulate many terminal features of a neuron, they
are not regulatory endpoints (Figure 4). Some
targets of terminal selectors are transcription
factors themselves, and these may further diversify individual neuron classes. Two examples,
one in invertebrates and one in vertebrates,
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COREGULATION OUTSIDE
THE NERVOUS SYSTEM
Terminal selectors are not restricted to the
nervous system. The coregulation of terminal differentiation genes by a small number
of transcriptional drivers has many precedents
(Davidson 2006). For example, the mouse Pax5
homeobox gene is a terminal selector for a
specic B cell type in the immune system
(Cobaleda et al. 2007), and shavenbaby is a
terminal selector for a specic type of epidermal cells in Drosophila (Chanut-Delalande
et al. 2006). In fact, grouping functionally
related genes into regulons is an ancient
and broadly applied gene regulatory strategy. Bacteria, for example, respond to specic
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modulation of their cis-regulatory inputs. Another driver for evolutionary change is mutations in the cis-regulatory regions of terminal
differentiation genes themselves, which lead to
the loss of or recruitment of a terminal differentiation gene into a terminal selector regulon
(Erwin & Davidson 2009).
FUTURE CHALLENGES
In spite of promising leads, a strong need
remains to further map regulons within individual neuron types in simple and accessible
model systems such as C. elegans. Such mapping
should entail not only genes expressed in specic neuron types but also broadly expressed
neuronal genes. In vertebrates, the identication of terminal selector regulons will remain
more challenging. The greater genomic complexity of vertebrates complicates the search
for discrete cis-regulatory elements through
transgenic reporter gene approaches because a
wider distribution of multiple terminal selector
binding sites over larger genomic intervals
may render the isolation of discrete functional
units difcult. A recent cis-regulatory analysis
of gene expression in dopaminergic neurons in
zebrash is consistent with such a complication
(Fujimoto et al. 2011). In such cases it may be
more useful to identify regulons not from the
cis-regulatory angle but from the trans-acting
angle through ChIP of transcription factors
whose maintained expression and genetic
requirement for terminal differentiation make
them good terminal selector candidates (such
as the Gata2, Tlx, or Runx genes mentioned
above). The in-depth analysis of the abovementioned vertebrate terminal selectors Crx,
Pet-1, Nurr1, and Pitx-3, which has involved
loss-of-function analysis, transcriptome analysis, bioinformatics, and chromatin immunoprecipitation, sets the stage for such future analysis.
DISCLOSURE STATEMENT
The author is not aware of any afliations, memberships, funding, or nancial holdings that might
be perceived as affecting the objectivity of this review.
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ACKNOWLEDGMENTS
Work from my laboratory cited in this review is funded by the NIH (R01NS039996-05;
R01NS050266-03) and the Howard Hughes Medical Institute. I thank members of the Hobert
lab, Evan Deneris, and Joseph Corbo for comment on this manuscript.
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Looking Back
Martin Raff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Membrane Protein Insertion at the Endoplasmic Reticulum
Sichen Shao and Ramanujan S. Hegde p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
Control of Organelle Size: The Golgi Complex
Debrup Sengupta and Adam D. Linstedt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p57
Dynamin: Functional Design of a Membrane Fission Catalyst
Sandra L. Schmid and Vadim A. Frolov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79
The Role of Atg Proteins in Autophagosome Formation
Noboru Mizushima, Tamotsu Yoshimori, and Yoshinori Ohsumi p p p p p p p p p p p p p p p p p p p p p p p 107
Principles of Unconventional Myosin Function and Targeting
M. Amanda Hartman, Dina Finan, Sivaraj Sivaramakrishnan,
and James A. Spudich p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 133
Force Generation, Transmission, and Integration during Cell
and Tissue Morphogenesis
Thomas Lecuit, Pierre-Francois Lenne, and Edwin Munro p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 157
Degrading Devices: Invadosomes in Proteolytic Cell Invasion
Stefan Linder, Christiane Wiesner, and Mirko Himmel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
Membrane-Anchored Serine Proteases in Vertebrate Cell
and Developmental Biology
Roman Szabo and Thomas H. Bugge p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 213
Wound Repair: Toward Understanding and Integration of Single-Cell
and Multicellular Wound Responses
Kevin J. Sonnemann and William M. Bement p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 237
Transmembrane Collagen Receptors
Birgit Leitinger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 265
Cooperation Between Integrins and Growth Factor Receptors
in Signaling and Endocytosis
Johanna Ivaska and Jyrki Heino p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291
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