Department of Biology, Brandeis University, 415 South Street, Brandeis, MA 02454, USA
* Author for correspondence (e-mail: sengupta{at}brandeis.edu)
Accepted 14 February 2005
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SUMMARY |
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Key words: C. elegans, Aristaless/Arx, Chemosensory neurons, Motoneurons, GABAergic
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Introduction |
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The functions of the highly conserved paired-type HD protein Aristaless
(AL) was first described in Drosophila
(Campbell and Tomlinson, 1998;
Campbell et al., 1993
;
Schneitz et al., 1993
). In
al mutants, the development of wings, legs and aristae, terminal
antennal appendages required for auditory functions and hygrosensation
(Gopfert and Robert, 2002
;
Manning, 1967
;
Sayeed and Benzer, 1996
) are
affected. AL was shown to act in a network with the Bar HD and LIM1 LIM-HD
proteins to regulate development of the pretarsus, the distal-most leg segment
(Kojima et al., 2000
;
Pueyo and Couso, 2004
;
Pueyo et al., 2000
;
Tsuji et al., 2000
).
Vertebrate genomes encode multiple AL homologs that have been classified into
three groups based on structural and functional properties, and expression
patterns: group I genes are primarily involved in skeletal and craniofacial
morphogenesis; group II genes are expressed in the central and peripheral
nervous system; and group III genes mediate diverse functions
(Meijlink et al., 1999
).
Recently, the functions of Arx, a group II murine and human homolog
of Al, have been described. In mice, knockout of Arx results
in animals with thin cerebral cortices, owing to decreased neuroblast
proliferation in the neocortical ventricular zone, and defects in the
differentiation, proliferation and migration of GABAergic interneurons from
the ganglionic eminences to the cortex and olfactory bulbs
(Kitamura et al., 2002
;
Yoshihara et al., 2005
).
Interestingly, mutations in the human ARX gene have been associated
with highly pleiotropic developmental and behavioral anomalies. These include
X-linked lissencephaly with abnormal genitalia (XLAG), mental retardation,
infantile spasms and epilepsy (Bienvenu et
al., 2002
; Stromme et al.,
2002a
; Stromme et al.,
2002b
). In both mice and humans, Arx is expressed at high
levels in the neocortical ventricular zone and in GABAergic interneurons in
the ganglionic eminences (Bienvenu et al.,
2002
; Colombo et al.,
2004
; Kitamura et al.,
2002
; Miura et al.,
1997
; Poirier et al.,
2004
). These results suggest that ARX plays an important role in
regulating both neuroblast proliferation and differentiation and migration of
GABAergic interneurons. However, the targets of ARX and its precise roles in
neuronal development remain to be elucidated. Because, together with Fragile X
syndrome, mutations in Arx may represent the most common cause of
mental retardation in males (Sherr,
2003
), it is important that the functions of ARX-related proteins
are further investigated.
C. elegans provides an excellent model system in which the
functions of conserved proteins can be genetically explored. In particular,
the roles of specific proteins in the development and function of the nervous
system can be easily investigated. The adult C. elegans hermaphrodite
contains 302 neurons of which 32 are sensory and 26 are GABAergic motoneurons
(McIntire et al., 1993b;
Ward et al., 1975
;
White et al., 1986
). Molecules
and pathways required for the generation and specification of sensory and
motoneuron subtypes have been described
(Melkman and Sengupta, 2004
;
Thor and Thomas, 2002
). Genes
identified to date encode members of well-conserved transcription factor
families, including members of several HD protein families. For example,
members of the OTX-type and LIM-HD protein families have been shown to play
roles in the development and differentiation of several sensory neuron types
in C. elegans (Lanjuin and
Sengupta, 2004
; Melkman and
Sengupta, 2004
). Vertebrate Otx genes can functionally substitute
for C. elegans Otx genes, suggesting conservation of protein function
across species (Lanjuin et al.,
2003
). Similarly, the mouse PITX2 HD protein has been shown to
functionally substitute for the C. elegans UNC-30 PITX-type HD
protein in the regulation of expression of the glutamic acid decarboxylase
gene and differentiation of GABAergic motoneuron subtypes
(Eastman et al., 1999
;
Jin et al., 1994
;
Jin et al., 1999
;
McIntire et al., 1993a
;
Westmoreland et al., 2001
).
Characterization of additional molecules required for the development of these
neuron types not only allows us to understand the principles underlying the
generation of distinct neuronal subtypes in an organism, but also provides an
opportunity to explore further the roles of conserved proteins in a
well-defined system.
Here, we describe characterization of the C. elegans homolog of Arx/Al, alr-1 (Aristaless/Arx-related). alr-1 mutants exhibit defects in the specification of the AWA and ASG chemosensory neurons, and we show that similar to its ortholog in Drosophila, ALR-1 acts in a pathway with the LIM1 ortholog LIN-11 to regulate the development of both these neuron types. Intriguingly, we also demonstrate that ALR-1 plays a role in the differentiation of GABAergic motoneurons. In alr-1 mutants, the VD MN type is mis-specified, leading to a partial adoption of DD motoneuron subtype characteristics. These data indicate that some functions of ARX/Aristaless may be conserved across species, and suggest that studying the role of ALR-1 in neuronal development in C. elegans may provide insights into the functions of this important protein in other organisms.
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Materials and methods |
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Expression of the following stably integrated markers was also examined in
alr-1 mutants (neuron type examined is indicated in parentheses):
gcy-8::gfp (AFD), srh-142::dsRed (ADF), str-1::gfp
(AWB), str-2::gfp (AWC), sre-1::gfp (ADL),
sra-6::gfp (ASH and ASI), str-3::gfp (ASI),
daf-7::gfp (ASI), odr-1::dsRed (AWC and AWB),
ttx-3::gfp (AIY) (Hobert et al.,
1997; L'Etoile and Bargmann,
2000
; Peckol et al.,
2001
; Ren et al.,
1996
; Troemel et al.,
1995
; Troemel et al.,
1997
; Troemel et al.,
1999
; Yu et al.,
1997
) (E. R. Troemel, PhD thesis, University of California,
1999).
Isolation, mapping and cloning of alr-1
oy42 and oy56 alleles were isolated in EMS mutagenesis
screens for altered expression of an integrated odr-7::gfp transgene
(kyIs38) or dye-filling defects respectively. The ok545
allele was generated by the C. elegans Gene Knockout Consortium.
Mutants were outcrossed at least four times prior to further analysis.
alr-1(oy42) was mapped with respect to genetic markers, polymorphisms
and deficiencies to LG X. Rescue of tested alr-1 mutant phenotypes
was obtained with sequences amplified from the cosmid R08B4 (nucleotides
13223-19971). The molecular nature of the lesions in the alr-1
alleles was determined by sequencing.
Expression constructs and generation of transgenic animals
The alr-1p::alr-1 and alr-1p::Al constructs were
generated by fusing 2.8 kb of alr-1 upstream promoter sequences to
Al or alr-1 cDNAs (gifts of G. Campbell and Y. Kohara,
respectively) in a C. elegans expression vector (gift of A. Fire).
The unc-30p::alr-1 construct was generated by fusing 2.5 kb of
unc-30 promoter sequences upstream of an alr-1 cDNA.
unc-30p::unc-55 was a gift from W. Walthall.
Germline transformations were performed using standard techniques
(Mello and Fire, 1995). All
transgenes were injected at 30 ng/µl along with one of the following
co-injection markers: 100 ng/µl pRF4 rol-6(su1006), 50 ng/µl
unc-122::gfp (Miyabayashi et al.,
1999
) or unc-122::dsRed.
Cell/lineage autonomy of ALR-1 function
A rescuing alr-1 genomic fragment was injected along with
osm-6::dsRed (gift of A. Lanjuin) at 15 ng/µl each into an
alr-1(oy42) strain containing stably integrated copies of an
odr-10::gfp fusion gene (kyIs37). L1-L3 larvae were
incubated in 1:500 dilution of DiO for 1 hour.
osm-6::dsRed-expressing animals were scored for the presence or
absence of odr-10::gfp expression, and the corresponding presence or
absence of osm-6::dsRed expression in ASI or ASK neurons on the same
side. Presence of the array scored as a result of perdurance of
osm-6::dsRed expression is unlikely as we could detect expression in
either of the lineally related ASK or ADL neurons on a given side. It is
possible that the number of AWA neurons lacking odr-10::gfp
expression is an overestimation, as gfp in the AWA neurons was often
difficult to detect in the background of fluorescence because of
dsRed expression and dye filling.
Behavioral assays
Single animal olfactory assays
Animals with the desired odr-7::gfp-expressing phenotype were
selected under 400x magnification, and allowed to recover on food for at
least 2 hours prior to analysis. Single animals were assayed essentially as
described (Bargmann et al.,
1993). The behavior was scored as wild type if the animal entered
a region of defined diameter surrounding the odorant without entering a
similar region around the control diluent during the course of the assay.
Statistical significance was determined using a chi-square test.
Dye-filling
Animals were incubated in 1:100 DiI or 1:1000 DiO in M9 for 2 hours, washed
twice and let recover on food for at least 30 minutes prior to analysis.
Dauer assays
Dauer assays were performed essentially as previously described
(Lanjuin and Sengupta,
2002).
Osmotic avoidance assays
Worms were placed on one half of a 5 cm plate surrounded by a barrier of 4M
fructose with a point source of an attractive odorant on the opposite side.
The percentage of worms that stayed within the barrier was scored after 30
minutes.
Generation of anti-ALR-1 antibodies and immunocytochemistry
Sequences encoding the C-terminal 182 amino acids of ALR-1 were cloned into
the pGEX4T-1 (Pharmacia) vector. The fusion protein was expressed in E.
coli and purified using Glutathione Sepharose beads. Polyclonal
antibodies were generated in rats by Cocalico Biologicals. Sera were affinity
purified before use. Staining with anti-ALR-1, anti-ODR-7 and anti-GABA
antibodies was performed as described
(McIntire et al., 1992;
Sarafi-Reinach et al., 2001
).
Animals were viewed under a Zeiss Axioplan microscope equipped with
epifluorescence and images were captured using a CCD camera (Hamamatsu).
Images were analyzed using Openlab (Improvision) and Adobe Photoshop software
(Adobe Systems).
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Results |
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ALR-1 regulates the differentiation of, and represses an AWA-like fate in, the ASG lineal sibling neurons
The AWA olfactory and the ASG chemosensory neurons arise from the terminal
cell division of the ABpl/raapapaa precursors
(Sulston et al., 1983). To
determine whether mutations in ALR-1 also affect differentiation of the
sibling ASG neurons, we examined expression of the markers
ops-1::dsRed and unc-30::gfp in alr-1 mutants.
Expression of both markers in the ASG neurons was affected in alr-1
mutants (Table 1). Similar to
the defects observed in the AWA neurons, marker expression was lost in one or
at a lower penetrance, in both ASG neurons. However, we did not detect ectopic
expression of either marker. To determine whether gene expression defects in
the AWA and ASG sibling neurons were correlated, we examined the expression of
both odr-7::gfp and ops-1::dsRed in individual
alr-1 mutant animals. As shown in
Table 2, loss of marker
expression in an AWA or ASG neuron was not correlated with loss of expression
in its sibling.
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ALR-1 acts in a parallel pathway with the forkhead domain protein UNC-130 to specify AWA and ASG fates
The forkhead domain-containing protein UNC-130 has previously been shown to
regulate asymmetric division of the AWA/ASG precursors
(Sarafi-Reinach and Sengupta,
2000). Similar to alr-1 mutants, the ASG neurons fail to
express ASG-like characteristics, and instead adopt an AWA-like fate in
unc-130 mutants. Expression of AWA-specific markers is also lost at a
low penetrance in unc-130 mutants. To determine whether ALR-1 and
UNC-130 act in a linear or parallel pathway to regulate AWA and ASG
development, we examined AWA- and ASG-specific gene expression in unc-130;
alr-1 double mutants. We observed an almost complete loss of
odr-7 expression in unc-130(ev505); alr-1(oy42) and
unc-130(ev505); alr-1(oy56) double mutants
(Table 3). We also observed a
significant increase in the penetrance of loss of ops-1::dsRed
expression in unc-130(ev505); alr-1(oy42) double mutants when
compared with either single mutant alone
(Table 3). These results
suggest that ALR-1 and UNC-130 act in parallel to specify AWA and ASG
fates.
|
To investigate possible regulatory relationships between ALR-1 and LIN-11,
we examined AWA- and ASG-specific gene expression in double mutants. We found
that odr-7 and ops-1::dsRed expression was lost to a similar
extent in lin-11(n389); alr-1(oy42) double mutants as in
lin-11(n389) mutants alone (Table
3), suggesting that ALR-1 and LIN-11 act in a linear pathway to
regulate gene expression in the AWA and ASG neurons. In both neuron types, a
higher percentage of lin-11(n389) than alr-1(oy42) mutants
exhibited loss of gene expression, indicating that genes in addition to
alr-1 may play a role in regulating lin-11. Alternatively,
lin-11 may function upstream of alr-1 and additional genes
to regulate AWA and ASG fate. To investigate whether ALR-1 acts upstream or
downstream of lin-11, we examined the expression of a stably
integrated lin-11::gfp fusion gene in alr-1 mutants. We
noted that 15% of alr-1(oy42) (n=87) when compared with
0% of wild-type AWA neurons (n=26) exhibited persistent expression of
lin-11::gfp through late larval stages. We also observed loss of
lin-11::gfp expression in 40% of ASG neurons of alr-1(oy42)
mutants (n=87). Taken together with the observation that
alr-1 expression was not detected in postmitotic neurons (see below),
these results suggest that, ALR-1 acts upstream of lin-11 in part to
downregulate lin-11 expression in later larval stages in the AWA
neurons, whereas ALR-1 promotes lin-11 expression in the ASG neurons.
Interestingly, Lim1, the Drosophila ortholog of
lin-11 has been shown to be regulated by AL and acts together with AL
to regulate the development of the distal-most compartment of the leg
(Pueyo and Couso, 2004
;
Pueyo et al., 2000
;
Tsuji et al., 2000
).
To further investigate the proposed regulatory relationships among alr-1, lin-11 and unc-130, we also examined marker expression in lin-11; unc-130 double mutants. In both AWA and ASG neurons, we observed a highly penetrant loss of marker expression in lin-11(n389); unc-130(ev505) double mutants (Table 3), consistent with the hypothesis that ALR-1 functions in a linear pathway with LIN-11 but in a parallel pathway with UNC-130 to regulate cell fate.
alr-1 is expressed in a spatiotemporally dynamic manner in neuronal and non-neuronal cells
To examine the expression pattern of ALR-1, we raised polyclonal antibodies
against the less well-conserved C-terminal sequences of ALR-1. Staining was
first evident in 1.5-fold embryos (Fig.
4B) and although the spatial expression was dynamic, stained
neuronal and non-neuronal cells were also observed at later embryonic stages.
In larvae and adults, ALR-1 expression was observed in multiple neuronal and
non-neuronal cells (including epidermal cells) in the head, neuronal cells in
the tail and in the GABAergic DD and VD motoneurons (MNs) in the ventral nerve
cord (Fig. 4F,H). Consistent
with ALR-1 being a transcription factor, expression was exclusively nuclear in
all observed cell types. No staining was observed in alr-1(oy42)
mutants (data not shown). To determine whether ALR-1 was expressed in the AWA
and ASG neurons, we examined colocalization of anti-ALR-1 staining with
expression of odr-7::gfp and ops-1::dsRed, which are
expressed postmitotically. However, we did not observe colocalization with
these markers in threefold embryos, larvae or adults
(Fig. 4I,J; data not shown),
although transient expression cannot be ruled out. As ARX has been shown to be
expressed in and required for the differentiation of GABAergic neurons in
vertebrates (Colombo et al.,
2004; Kitamura et al.,
2002
; Poirier et al.,
2004
), and ALR-1 is expressed in the GABAergic ventral cord
motoneurons, we further investigated whether ALR-1 is expressed in additional
GABAergic cells by examining colocalization of anti-ALR-1 staining with
unc-47::gfp expression. unc-47 encodes a vesicular GABA
transporter and is expressed in all GABAergic neurons
(McIntire et al., 1997
).
Intriguingly, we observed ALR-1 expression in 24 of 26 GABAergic neurons,
including the 13 VD and 6 DD, and the RME L/R, AVL, RIS and DVB neurons
throughout postembryonic development (Fig.
4F,H; data not shown).
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The ASI chemosensory neurons are lineally related to the AWA and ASG
neurons such that these three neuron types arise from the common ABp(l/r)aapap
precursors via two (AWA and ASG) or three (ASI) additional cell divisions
(Fig. 5A)
(Sulston et al., 1983).
Additional cells arising from these precursors include the AIB interneurons
and a cell that undergoes programmed cell death. The ASI neurons can be
relatively easily identified via their characteristic cell body positions and
via filling with lipophilic dyes (Perkins
et al., 1986
; White et al.,
1986
). An additional chemosensory cell type that also fills with
dye and is easily identified is the ASK neuron, which arises from a more
lineally distant precursor (Fig.
5A) (Sulston et al.,
1983
). We reasoned that if alr-1 acts in the AWA/ASG/ASI
lineage, presence or absence of odr-10::gfp expression in the AWA
neurons should correlate more highly with the presence or absence of
alr-1 rescuing sequences in the lineally related ASI neurons than in
the ASK neurons. However, if alr-1 acts elsewhere, then we may detect
higher correlation with the presence or absence of alr-1-coding
sequences in ASK (if alr-1 acts in this lineage) or similar
correlation with expression in both cell types (if alr-1 acts in a
distinct lineage).
|
VD motoneurons adopt partial DD motoneuron characteristics in alr-1 mutants
We next investigated whether the development of GABAergic neurons was
affected in alr-1 mutants. As the development of the 13 VD and 6 DD
ventral cord motoneurons has been studied extensively, we focused our
attention on these cell types. We observed ectopic expression of the DD
MN-specific marker, flp-13::gfp
(Kim and Li, 2004) in all
alleles of alr-1 mutant animals
(Table 4;
Fig. 6D). On average, there
were 10-13 flp-13::gfp-expressing cells in alr-1 mutant
adults when compared with six in wild-type adults. All
flp-13::gfp-expressing cells were stained with anti-GABA antibodies
indicating that the additional cells were GABAergic
(Table 4; Fig. 7). However, the total
number of GABAergic MNs in the ventral nerve cord were unaltered in
alr-1 mutants as determined by expression of an unc-25
glutamic acid decarboxylase fusion gene
(Jin et al., 1999
), and by
staining with anti-GABA antibodies (Table
4). These results indicated the possibility that the 13 GABAergic
VD MNs were adopting DD MN characteristics in alr-1 mutants. Unlike
the DD MNs, which are generated embryonically, the VD MNs are born
postembryonically at the L2 larval stage
(Sulston, 1976
;
Sulston and Horvitz, 1977
;
Sulston et al., 1983
). Ectopic
flp-13::gfp-expressing cells in alr-1 mutants were not
observed prior to the L2 larval stage
(Table 4,
Fig. 6H), further suggesting
that the VD MNs were expressing DD MN-specific genes in alr-1
mutants. Consistent with this hypothesis, markers for other MNs (DA and DB,
unc-129::gfp; VA and VB, del-1::gfp; VC,
ida-1::gfp) were unaffected in alr-1 mutants (data not
shown).
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ALR-1 acts in parallel to the UNC-55 COUP-TF-like nuclear hormone receptor to specify VD MN features
The UNC-55 COUP-TF-like nuclear hormone receptor has been shown to be
expressed in the VD MNs, where it acts to repress DD MN identity
(Walthall and Plunkett, 1995;
Zhou and Walthall, 1998
). In
unc-55 mutants, the VDs adopt a DD wiring pattern, and this change in
innervation pattern is believed to underlie the locomotion defects of
unc-55 mutants (Walthall and
Plunkett, 1995
; Zhou and
Walthall, 1998
). In agreement with a VD-to-DD fate transformation
in unc-55 mutants, we observed ectopic flp-13::gfp
expression in unc-55(e402) mutant adults but not in L1 larvae
(Fig. 6F,I;
Table 4) (Shan et al., 2005
). ALR-1 may
act downstream or upstream of, or in parallel to UNC-55 to regulate MN
differentiation. However, alr-1 expression in the MNs was unaffected
in unc-55(e402) mutants (an average of 18±1 ALR-1-expressing
cells were observed in unc-55(e402) when compared with 18±2 in
wild-type animals; n>22 each). Similarly,
unc-55::gfp expression was also unaffected in
alr-1(oy42) mutants (an average of 14±6
unc-55::gfp-expressing cells were observed in
alr-1(oy42) when compared with 13±5 in wild-type animals;
n>100 each), suggesting that UNC-55 and ALR-1 may act in parallel
to repress flp-13::gfp expression in the VD MNs. As ALR-1 is
expressed in both the VD and DD MNs, whereas UNC-55 is expressed only in the
VD MNs, we next determined whether ectopic expression of UNC-55 in the DD MNs
was sufficient to repress flp-13::gfp expression. However, the
expression pattern of flp-13::gfp was unaltered in transgenic animals
expressing unc-30::unc-55 (Table
4). These results suggest that both UNC-55 and ALR-1 are necessary
to repress flp-13::gfp expression in the VD MNs, but are not
sufficient to repress expression in the DD MNs.
alr-1 mutants exhibit additional pleiotropies
Consistent with alr-1 expression in multiple neuronal and
non-neuronal cell types, alr-1 mutants exhibit additional phenotypes.
A subset of sensory neurons in the amphid and phasmid sensory organs fill with
lipophilic dyes such as DiI (Perkins et
al., 1986). Developmental or structural defects in either the
supporting sheath and socket cells or in the sensory neurons result in
dye-filling defects (dyf phenotype). Ninety-three and 34% of
alr-1(oy42) mutant amphids and phasmids, respectively
(n=224), exhibited dye-filling defects. Consistent with a defect in
the supporting non-neuronal cells, dye filling was affected in an all-or-none
manner, such that either all amphid neurons on one side of an alr-1
mutant animal failed to dye fill or all neurons dye filled in the wild-type
pattern. dyf mutants exhibit additional pleiotropies such as the
inability to avoid osmotic shock (Osm phenotype) and failure to enter the
alternate dauer developmental stage (Daf-d phenotype)
(Starich et al., 1995
).
alr-1 mutants are both Osm [
65% of alr-1(oy42) and 61%
of alr-1(oy56) mutants (n>100) failed to avoid a high
osmolarity solution] and Daf-d [15% alr-1(oy42) and 13% of
alr-1(oy56) animals formed dauers under conditions where 75% of
wild-type animals form dauers (n>200)]. Taken together with the
observation that the differentiation of dye-filling neurons appeared to be
unaffected in alr-1 mutants, these results suggest that the Dyf
phenotype may be due to defects in the amphid sheath or socket cells. These
defects may be structural, as the expression of a subset of sheath and socket
cell differentiation markers was unaltered in alr-1 mutants (data not
shown). It is unlikely that the AWA and ASG differentiation and/or generation
defects are a secondary consequence of the defects in the amphid support
cells, as the Dyf phenotype was not correlated with the defects in either gene
expression or morphology of the AWA and ASG neurons. In addition, ODR-7
expression was unaltered in daf-6(e1377) and che-14(e1960)
mutants, which exhibit defects in the development of the amphid support cells
and additional hypodermal cells (Albert et
al., 1981
; Michaux et al.,
2000
) (data not shown). Thus, ALR-1 may affect the differentiation
of both a subset of sensory neurons, as well as the supporting non-neuronal
cells.
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Discussion |
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Role of ALR-1 in GABAergic motoneuron development
alr-1 is expressed in 24 out of 26 GABAergic neurons in C.
elegans, suggesting a role for this gene in GABAergic neuron development
and/or function. Although we did not detect gross abnormalities in the
development of additional ALR-1 expressing GABAergic neurons in alr-1
mutants, we have shown that alr-1 may play a role in the
differentiation of the VD motoneurons. The inhibitory VD (DD) MNs innervate
the ventral (dorsal) body muscles and are in turn innervated by excitatory
cholinergic MNs which also innervate dorsal (ventral) body wall muscles
(White et al., 1986). Thus,
alternate contraction of ventral or dorsal muscles is accompanied by
relaxation of dorsal or ventral muscles respectively, resulting in the
characteristic sinusoidal locomotory motion
(McIntire et al., 1993a
;
McIntire et al., 1993b
;
White et al., 1986
). The
D-type MNs may also regulate wave amplitude
(McIntire et al., 1993b
).
The GABAergic DD motoneuron marker flp-13 is ectopically expressed
in the VD MNs in alr-1 mutants, whereas expression of additional
GABAergic markers, common to both VD and DD motoneurons is unaffected. In
addition, the synaptic connectivities of the VD MNs were also unaltered. We
could not further investigate the extent to which the differentiation of the
VD MNs was affected in alr-1 mutants, owing to the lack of additional
VD- or DD-specific markers. The flp-13 gene is predicted to encode at
least six FMRFamide-related neuropeptides
(Li et al., 1999), two of
which have been biochemically isolated from C. elegans
(Li et al., 1999
;
Marks et al., 2001
). Peptides
encoded by flp-13 have been shown to cause a dramatic inhibition of
locomotory behavior and paralysis when injected into Ascaris suum,
and inhibit pharyngeal activity in C. elegans
(Marks et al., 2001
;
Rogers et al., 2001
),
suggesting that these neuropeptides may act to modulate the inhibitory
functions of GABA at the neuromuscular junction. Restriction of
flp-13 expression to the DD MNs in wild-type animals may be important
for precise modulation of locomotory behaviors under specific conditions.
The COUP transcription factor UNC-55 has been previously shown to prevent
the expression of the DD synaptic pattern in the VD MNs
(Walthall and Plunkett, 1995;
Zhou and Walthall, 1998
). We
have shown that similar to ALR-1, UNC-55 also represses expression of
flp-13::gfp in the VD MNs, although, unlike UNC-55, ALR-1 does not
affect the synaptic pattern of VD motoneurons. ALR-1 is not sufficient to
repress flp-13 expression in the absence of UNC-55 function and vice
versa, suggesting that functions of both proteins are necessary for repression
of flp-13 expression in the VD MNs. Thus, ALR-1 acts together with a
member of the well-conserved COUP transcription factor family to regulate the
differentiation of a specific GABAergic MN subtype
(Fig. 8B). However, mutations
in unc-55 do not affect AWA development, and mutations in
unc-130 and lin-11 do not alter flp-13::gfp
expression (T.M. and P.S., unpublished), suggesting that ALR-1 functions in
different pathways to regulate chemosensory and motoneuron development.
Implications for ARX function in vertebrates
Our results indicate that ALR-1 acts in distinct transcriptional cascades
to regulate asymmetric cell division of a neuronal precursor and to specify
the characteristics of a GABAergic MN subtype in C. elegans
(Fig. 8). These processes have
parallels to the processes regulated by ARX in vertebrates. In arx
mutant mice, neuroblast proliferation in the cerebral cortex is decreased
(Kitamura et al., 2002).
Neuroblast proliferation in the ventricular zone occurs via temporally
regulated symmetric and asymmetric cell divisions that generate additional
neuronal precursors and postmitotic neurons
(McConnell, 1995
). We
speculate that ARX may regulate these cell divisions perhaps by regulating the
localization or segregation of determinants such as Numb or Notch
(Petersen et al., 2002
;
Shen et al., 2002
;
Wakamatsu et al., 1999
;
Zhong et al., 1996
;
Zhong et al., 2000
;
Zhong et al., 1997
). ALR-1
acts in part by temporally restricting expression of lin-11 in the
AWA neurons, and by promoting lin-11 expression in the ASG neurons.
Interestingly, expression of the LIM homeobox genes Lhx6 and
Lhx9 is abolished in the neocortex and thalamic eminence,
respectively, in Arx mutant mice, whereas the domain of Lhx6
expression in the ganglionic eminences is enlarged
(Kitamura et al., 2002
). Taken
together with the observation that lim1 and al function in a
network to regulate Drosophila leg development
(Pueyo and Couso, 2004
;
Pueyo et al., 2000
;
Tsuji et al., 2000
), these
findings suggest that regulatory mechanisms between ARX proteins and LIM-HD
proteins may be conserved across species.
ALR-1 acts together with the UNC-55 COUP transcription factor to regulate
the differentiation of a GABAergic MN type in C. elegans. A COUP-TF
protein and the PRDL-B Aristaless/ARX homolog have been shown to act in a
network to regulate neurogenesis in Hydra
(Gauchat et al., 2004). In
vertebrates, COUP transcription factors have been implicated in neurogenesis,
neuronal differentiation, migration and axonal guidance
(Qiu et al., 1997
;
Tripodi et al., 2004
;
Zhou et al., 1999
;
Zhou et al., 2001
).
Interestingly, COUP-TFI and COUP-TFII exhibit overlapping spatiotemporal
expression patterns with ARX in the developing neocortex, as well as in the
lateral and medial ganglionic eminences, which give rise to GABAergic
interneurons (Jonk et al.,
1994
; Liu et al.,
2000
; Qiu et al.,
1994
). Moreover, COUP-TFI is co-expressed with the GABAergic
neuron marker calbindin in the cortex
(Tripodi et al., 2004
). These
findings suggest the intriguing possibility that COUP and ARX function
together to regulate neuronal, and in particular GABAergic, neuronal
development. Our results suggest that ARX proteins function in partly
conserved genetic networks to regulate the development of different tissue and
cell types in different species, and raise the possibility that identification
of potential interactors and targets of ALR-1 in C. elegans may aid
in elucidating ARX function in brain development in vertebrates.
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ACKNOWLEDGMENTS |
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