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First published online May 1, 2006
doi: 10.1242/10.1242/dev.02359
Review |
1 Plant Molecular Biology Laboratory, Institute of Biotechnology, POB 56,
FI-00014, University of Helsinki, Finland.
2 Department of Biology, FI-20014, University of Turku, Finland.
3 Umeå Plant Science Centre, Department of Forest Genetics and Plant
Physiology, Swedish University of Agricultural Sciences, SE-901 83,
Umeå, Sweden.
Author for correspondence (e-mail:
yhelariu{at}mappi.helsinki.fi)
SUMMARY
Hormonal signalling plays a pivotal role in almost every aspect of plant development, and of high priority has been to identify the receptors that perceive these hormones. In the past seven months, the receptors for the plant hormones auxin, gibberellins and abscisic acid have been identified. These join the receptors that have previously been identified for ethylene, brassinosteroids and cytokinins. This review therefore comes at an exciting time for plant developmental biology, as the new findings shed light on our current understanding of the structure and function of the various hormone receptors, their related signalling pathways and their role in regulating plant development.
Introduction
Plant hormones (phytohormones) are small organic molecules that affect
diverse developmental processes. Alterations in hormone responses have been
responsible for several important agricultural advances, such as the breeding
of semi-dwarf varieties and increased grain production
(Ashikari et al., 2005
;
Silverstone and Sun, 2000).
Unlike animal hormones, which are produced in specific organs, phytohormones
are typically produced throughout the plant (see
Box 1). Virtually every aspect
of plant development from embryogenesis to senescence is under hormonal
control. In general, this developmental control is exerted by controlling cell
division, expansion, differentiation and cell death. In this manner, diverse
developmental processes can be controlled, including formation of the
apical-basal and radial pattern, seed germination, determination of plant
architecture, flowering, fruit ripening and shedding.
In this review, we consider six classes of phytohormones that are key developmental regulators and for which the receptors are known (Table 1). This review will centre on the model plant Arabidopsis thaliana, as it is in this species that we best understand the receptors and processes involved in hormonal perception.
|
Indole-3-acetic acid (IAA), the major auxin in plants, was isolated in the
1920s from oat coleoptiles as a growth-promoting factor. More recently, auxin
has been shown to act as a signal for cell division, cell elongation and cell
differentiation, both during embryogenesis and in the mature plant
(Buchanan et al., 2000).
During embryogenesis, auxin signaling is instrumental in establishing
apical-basal polarity, and in the formation of the root and shoot apical
meristems and hypocotyls (Jenik and
Barton, 2005). However, it was only last year that the F-box
protein TRANSPORT INHIBITOR RESPONSE1 (TIR1) was identified as being an auxin
receptor (Dharmasiri et al.,
2005a; Kepinski and Leyser,
2005), and this finally gave a clear picture of auxin signal
transduction.
| Box 1. Plant hormones versus animal hormones Plant hormones
Animal hormones
|
Most of the components of the auxin signalling pathway have been identified
from genetic screens in Arabidopsis (for a review, see
Woodward and Bartel, 2005)
and TIR1 was no exception. It was originally identified as a series
of semi-dominant alleles from a screen based on tolerance to auxin transport
inhibitors in a root elongation assay
(Ruegger et al., 1997). It was
quickly observed that tir1 mutations affect auxin response rather
than auxin transport, as sensitivity to auxin was compromised in mutant plants
while polar auxin transport appeared normal
(Ruegger et al., 1998).
TIR1 encodes an F-box domain protein with leucine-rich repeats (LRRs)
that is similar to the S-phase kinase-associated protein (SKP2) from yeast
(Ruegger et al., 1998). Like
its yeast counterpart, TIR1 interacts with the scaffold protein cullin
(AtCUL1), with one of the SKP1-like proteins (ASK1/ASK2), and with the
ring-domain protein RBX1, to form an SCF-type ubiquitin-protein ligase complex
(Deshaies, 1999;
Gray et al., 1999;
Moon et al., 2004). Such
complexes ubiquitinate their substrates to target them for subsequent
degradation by the 26S proteasome (see Box
2). The core cullin, SKP1-like and RBX1 proteins provide the
catalytical activity necessary for the transfer of the activated ubiquitin to
the target protein, whilst target specificity is conferred by the F-box
protein (Gray et al.,
2001).
| Box 2. Degradation via ubiquitination
Underlying many developmental processes is the fundamental requirement to
selectively remove short-lived regulatory proteins. One way to achieve this is
through the marking of proteins destined for destruction with ubiquitin
(ubiquitination), followed by the recognition and catabolism of the
ubiquitinated proteins by the 26S proteasome
(Smalle and Vierstra, 2004
|
|
). The
Aux/IAAs are a gene family encoding short-lived, primary auxin-response
proteins (Dharmasiri and Estelle,
2004; Ulmasov et al.,
1997). These proteins cannot bind DNA directly but exert their
regulatory activity by repressing the transcriptional activities of a group of
AUXIN RESPONSE FACTORS (ARFs), which typically act as transcriptional
activators (Ulmasov et al.,
1999a; Ulmasov et al.,
1999b). Thus, for some years, a model has existed in which auxin
promotes Aux/IAA ubiquitination by the SCFTIR1 complex (see
Box 2), triggering Aux/IAA
degradation by the 26S proteosome and thereby releasing the ARFs from the
repressive effects of the Aux/IAA complex
(Fig. 1A,B).
The problem of how the presence of auxin phytohormones controlled this
process was solved only when TIR1 was identified as being a receptor for
auxin. Both Ottoline Leyser's and Mark Estelle's groups showed, by
immunoprecipitation of TIR1, that an auxin receptor co-purifies with TIR1, and
by using a protein pull-down with tagged Aux/IAAs, that the interaction
between SCFTIR1 and Aux/IAAs involves direct auxin binding
(Dharmasiri et al., 2005a;
Kepinski and Leyser, 2005).
Importantly, this auxin receptor activity was retained in in vitro assays in
which TIR1 was expressed in heterologous animal systems, and auxin binding in
these assays was dependent on the presence of TIR1
(Dharmasiri et al., 2005a;
Kepinski and Leyser, 2005).
Taken together with previous work, these data indicate that auxin promotes
SCFTIR1 - Aux/IAA interaction, by binding directly to TIR1, which
leads to Aux/IAA degradation and, consequently, to the de-repression of
ARF-dependent auxin responses (Dharmasiri
et al., 2005a; Kepinski and
Leyser, 2005) (Fig.
1A,B).
There are over 700 F-box proteins in Arabidopsis
(Gagne et al., 2002), although
TIR1 belongs to a small subfamily of seven related genes
(Dharmasiri et al., 2005b). As
strong loss-of-function tir1 mutants have only modest alterations in
auxin response and development, it is probable that genetic redundancy has
disguised strong phenotypes (Dharmasiri et
al., 2005b; Ruegger et al.,
1998). The quadruple mutant in which TIR1 and the three
most closely related genes, AUXIN SIGNALING F-BOX PROTEINS 1, 2 and
3 (AFB1-AFB3), are mutated has a more severe phenotype, and
this mutant combination is auxin insensitive. Additionally, each AFB protein
is able to interact with Aux/IAAs in an auxin-dependent manner, indicating
that auxin binding is collectively mediated by TIR1 and the AFB proteins
(Dharmasiri et al., 2005b).
This quadruple mutant represents a near complete loss of auxin response, and
it is therefore possible to assess the effect of severely diminished auxin
perception on plant development. The most severe quadruple mutants exhibit
embryonic phenotypes with failure to specify the root meristem
(Fig. 2B), similar to
gain-of-function mutations in Aux/IAAs or certain loss-of-function mutations
in ARFs (Dharmasiri et al.,
2005b). The less severe individuals exhibit defective hypocotyl
elongation, apical hook formation, lateral root formation, tropic responses,
root hair development and meristem organisation. Later in development, the
less severe quadruple mutant individuals display defective leaf morphology and
inflorescence architecture, including reduced apical dominance and size
(Fig. 2A). The phenotypic
variability and presence of some auxin signalling in the quadruple mutant may
be explained by either residual AFB activity (in the case that all the mutant
alleles are not null) or by the presence of other genes that encode auxin
receptors.
|
). One candidate
for such an extracellular receptor is the AUXIN BINDING PROTEIN1 (ABP1), as
changes in the ion transport associated with the early stages of auxin-induced
growth can be inhibited by extracellular treatment with anti-ABP1 antibodies
(Leblanc et al., 1999). Dwarfed rice plants and the gibberellin receptor
Gibberellins are tetracyclic diterpenoid phytohormones. They were first
identified in the 1930s as compounds that are produced by a fungus and that
cause excessive shoot elongation and reduced seed production in plants; they
have subsequently been implicated in several other processes, such as
promoting flowering and seed germination
(Buchanan et al., 2000).
Unlike the cytokinin, ethylene, brassinosteroid, abscisic acid and auxin
receptors, which were all identified first in Arabidopsis, the
gibberellin (GA) receptor was identified in rice by Makoto Matsuoka's
laboratory. A recombinant GIBBERELLIN INSENSITIVE DWARF1 (GID1) protein was
shown to bind radio-labelled gibberellin in in vitro assays
(Ueguchi-Tanaka et al.,
2005). GID1 shares homology with the hormone-sensitive lipase
(HSL) family and is encoded by a single gene in rice. However, in
Arabidopsis, it is represented by three, as yet, uncharacterised
genes. Although the receptor bears little resemblance to TIR1, the mechanism
of gibberellin perception and the response of a plant to it is somewhat
similar to that of auxin, in that it also targets proteins for destruction.
GID1 binds the SLENDER RICE (SLR1) protein
(Ikeda et al., 2001), a member
of the DELLA class of transcriptional repressors, directly in a
gibberellin-dependent manner
(Ueguchi-Tanaka et al.,
2005). These DELLA proteins may directly block the
gibberellin-dependent transcription of target genes, potentially in a similar
way to the blocking of auxin action by the Aux/IAAs
(Fig. 1C,D). The identification
of GA-related transcription factors will allow this hypothesis to be tested.
As a consequence of GID1 binding, SLR1 is then targeted for degradation. This
depends on the presence of a functional GID1 protein
(Ueguchi-Tanaka et al., 2005)
and most likely occurs through the recruitment of an SCFGID2
ubiquitin ligase complex, involving the F-box protein GID2
(Fig. 1C,D)
(Gomi et al., 2004;
Sasaki et al., 2003).
The rice gid1 mutant is inherited in a recessive manner,
confirming the biochemical data that the receptor is a positive regulator of
gibberellin signalling. The homozygous plant is unresponsive to gibberellins,
it is unable to produce fertile flowers and displays a severe dwarf phenotype
with wide, dark-green leaf blades
(Ueguchi-Tanaka et al., 2005)
(Fig. 2C), similar to other
GA-insensitive mutants (Sakamoto et al.,
2004). gid1 mutants also accumulate GA1, a gibberellin,
at about 95 times the level of wild-type plants, indicating that a feed-back
mechanism is involved in GA synthesis. Overexpression of GID1 produces tall
plants with long leaves, consistent with the phenotype of plants that are
given an overdose of gibberellins
(Ueguchi-Tanaka et al.,
2005). It will be interesting to compare the phenotype of
Arabidopsis plants carrying mutations in all three GID1
homologues, as well as GID1-overexpressing lines. Although GID1
homologues have only been characterised in rice, gain-of-function mutants in
Arabidopsis that affect the DELLA genes are reported to have similar
phenotypes to those observed in gain-of-function rice slr1 mutants
(Ikeda et al., 2001;
Peng et al., 1997). Similar to
the gain-of-function rice slr1 mutants
(Ikeda et al., 2001),
gai gain-of-function mutants of Arabidopsis lead to small
dwarfish plants that cannot be rescued by the addition of GA
(Peng et al., 1997). Whereas
in rice, SLR1 is the only DELLA protein, in Arabidopsis, the DELLA
family is represented by five members
(Bolle, 2004). Genetic
redundancy is likely to be responsible for the fact that Arabidopsis
DELLA loss-of-function mutants have only modest phenotypes compared with those
in rice. The rice slr1 mutant is tall and thin, and resembles plants
saturated with gibberellins (Ikeda et al.,
2001). GID2 homologues have been characterised in
Arabidopsis, and like loss-of-function mutations in GID2 of
rice, mutations in the Arabidopsis GID2 homologue sleepy1
(sly1) result in gibberellin-insensitive dwarf phenotypes and in the
accumulation of DELLA proteins. There is also biochemical evidence to support
the assembly of an Arabidopsis SCFSLY1 complex
(Dill et al., 2004;
Fu et al., 2004;
McGinnis et al., 2003).
Brassinosteroid receptors perceive plant steroids
Since brassinolide (BL), the most active brassinosteroid (BR), was isolated
in 1979, as a substance that promoted stem elongation, BRs have been
implicated in a range of biological processes, including seed germination,
stem elongation, leaf expansion and xylem differentiation
(Buchanan et al., 2000;
Cano-Delgado et al., 2004).
BRASSINOSTEROID INSENSITIVE1 (BRI1) was identified as a putative BR receptor
from a collection of alleles obtained through a genetic screen for
BR-insensitive Arabidopsis mutants in Joanne Chory's laboratory
(Li and Chory, 1997). These
alleles conferred a dwarf phenotype, similar to loss-of-function mutants for
BR biosynthesis, indicating that BRI1 is a positive regulator of
brassinosteroid signalling. BRI1 is a leucine-rich-repeat (LRR) receptor-like
kinase that has 24 LRRs separated by a 70-amino acid island in its
extracellular domain, a transmembrane domain and a functional cytoplasmic
serine/threonine kinase domain (Fig.
3A) (Friedrichsen et al.,
2000; Li and Chory,
1997). Binding of a BR to BRI1 was demonstrated by the in vitro
co-immunoprecipitation of BL with BRI1
(Wang et al., 2001). Later it
was shown that BL binds directly to the 70-amino acid island in the
extracellular domain between LRR21 and LRR22 of BRI1
(Kinoshita et al., 2005).
A second protein, BRI1-ASSOCIATED RECEPTOR KINASE (BAK1), which can
heterodimerize with BRI1, is also required for brassinosteroid signalling.
BAK1 was identified simultaneously in a genetic screen for constitutively
expressing lines that suppress the weak bri1-5 allele
(Li et al., 2002) and as a
BRI1-interacting protein in a yeast two-hybrid screen
(Nam and Li, 2002). Although
in one study, the heterodimerization of BRI1 and BAK1 was significantly
affected by BR levels (Wang et al.,
2005), ligand-independent heterodimerization of these two proteins
almost certainly occurs, as BRI1 and BAK1 have been shown to dimerize in yeast
cells without plant steroids, as well as in cowpea protoplasts
(Nam and Li, 2002;
Russinova et al., 2004).
Genetic analysis has also demonstrated a positive role for BAK1 in BR
signalling, as its overexpression can suppress a weak bri1 mutation.
Similarly, bak1 mutants resemble weak bri1 mutants and
enhance this phenotype in the double mutant
(Li et al., 2002;
Nam and Li, 2002). It is
unclear how this BRI1-BAK1 dimerization affects BR signalling. However, BRs do
stimulate the phosphorylation of both BRI1 and BAK1
(Wang et al., 2005;
Wang et al., 2001), and this
not only activates the kinase activity, but also may provide interaction sites
for downstream molecules.
The activation of the BRI1 and BAK1 receptor kinases that is stimulated by
BR binding leads to the dephosphorylation and accumulation of the nuclear
BR-response proteins BZR1 and BES1 (Wang
et al., 2002; Yin et al.,
2002), possibly by the inhibition of BIN2, a negative regulator of
the BR signalling pathway (Li and Nam,
2002) (Fig. 4).
BIN2 is protein kinase and a major signalling component in the brassinosteroid
pathway; semi-dominant bin2 mutants resemble bri1 mutants in
many aspects of development (Li et al.,
2001). In the absence of BR, BIN2 phosphorylates BZR1 and BES1,
thereby targeting them for degradation
(Fig. 4)
(He et al., 2002;
Zhao et al., 2002). BZR1
binds to specific DNA sequences and represses the transcription of BR
biosynthesis genes (He et al.,
2005). BES1 also binds specific DNA sequences in association with
the BIM protein and acts as a transcriptional activator for BR response genes
(Fig. 4)
(Yin et al., 2005). The
system may be further fine-tuned by the dephosphorylation of BES1 and BZR1 by
the phosphatase BSU1, in a manner that is antagonistic to BIN2
(Mora-Garcia et al.,
2004).
|
|
;
Li et al., 1996)
(Fig. 5A). In Arabidopsis,
BRI1 is represented by a small gene family comprising four members,
BRI1 and BRL1-BRL3 (Fig.
3A). BRL1 and BRL3, but not BRL2,
encode functional BR receptors that can bind BL and rescue the bri1
phenotype when ectopically expressed
(Cano-Delgado et al., 2004).
brl1 mutants display increased phloem and reduced xylem
differentiation. BRL1 and BRL3 have vascular-specific
expression patterns, and when mutations in all three receptors are combined,
the bri1 brl1 brl3 triple mutant shows enhanced dwarfism, as well as
an enhanced vascular phenotype that is more severe than that of any of the
single mutants (Cano-Delgado et al.,
2004). Ethylene receptors: negative regulators of ethylene signalling
The phytohormone ethylene is a simple, gaseous hydrocarbon molecule that
was identified 100 years ago as the active component that inhibits hypocotyl
elongation in dark-grown pea seedlings. In the following decades, ethylene was
shown to affect other developmental processes, such as the triggering of
abscission, fruit ripening, and the relaying of responses to external stress
factors, such as pathogen responses
(Buchanan et al., 2000). In
1993, Elliot Meyerowitz's laboratory cloned an ethylene receptor, ETHYLENE
RESPONSE 1 (ETR1), that shares similarities with the histidine kinases that
are common in prokaryotic signal transduction
(Box 3). It was the first plant
hormone receptor to be identified (Chang
et al., 1993; Schaller and
Bleecker, 1995). Subsequent genetic studies in
Arabidospsis revealed that ETR1 and four related ethylene receptors,
ETR2, ERS1 (ETHYLENE RESPONSE SENSOR), ERS2 and EIN4 (ETHYLENE INSENSITIVE),
operate as negative regulators of ethylene signalling
(Hua and Meyerowitz,
1998).
Dark-grown Arabidopsis seedlings respond to ethylene by inhibiting
hypocotyl and root elongation, and by thickening the hypocotyl and
exaggerating the apical hook of the shoot; together these constitute to the
so-called triple response (Fig.
5B). Many genes encoding ethylene signalling components, including
ETR1 (Bleecker et al.,
1988; Chang et al.,
1993), ETR2 (Sakai et
al., 1998) and EIN4
(Hua et al., 1998;
Roman et al., 1995), have been
identified from genetic screens based on altered effects to the triple
response (Fig. 5B). Mutations
in these loci result in plants with increased leaf size (largely due to cell
enlargement), and confer resistance to ethylene-induced leaf senescence. In
all cases, these mutations were dominant and mapped to a hydrophobic
ethylene-binding pocket of the receptor
(Schaller and Bleecker, 1995).
Some of these mutations abolished ethylene binding in yeast, suggesting that
the mutant receptors operate as dominant-negative regulators of ethylene
signalling in the absence of ethylene. Upon ethylene binding, the negative
activity of the receptors would be inactivated. Decisive evidence for the
negative regulatory role for these receptors on ethylene signalling was
obtained from the analysis of loss-of-function mutants
(Hua and Meyerowitz, 1998).
Single loss-of-function mutations had little or no effect on seedling growth,
indicating the existence of functional redundancy among the receptors.
However, double, triple and quadruple loss-of-function mutants exhibit
constitutive activation of ethylene responses, and the quadruple mutant showed
reduced leaf size due to a reduction in epidermal cell size.
|
;
O'Malley et al., 2005;
Schaller and Bleecker, 1995).
In addition to ethylene binding, the N-terminal hydrophobic domain of ETR1,
and presumably of the other receptors, is needed for targeting to the
endoplasmic reticulum (ER) (Chen et al.,
2002). Adjacent to the hydrophobic domain is a GAF domain of
unknown function (Fig. 3B). GAF
domains in other organisms have been shown to act as cGMP-specific
phosphodiesterases in a variety of signalling components
(Aravind and Ponting, 1997).
The C-terminal part of the ethylene receptors is involved in signal output,
and it shares some similarities with bacterial two-component histidine kinases
(Box 3). Only ETR1 and ERS1
contain all of the conserved residues that are required for histidine kinase
activity (Fig. 3B)
(Chang et al., 1993;
Hua et al., 1995).
Additionally, ETR1, ETR2 and EIN4 contain a receiver domain at the most
C-terminal part of the receptor. A conserved aspartate residue within the
receiver domain can putatively receive a phosphoryl group from a histidine
kinase.
Downstream of the ethylene receptors is CTR1 (CONSTITUTIVE TRIPLE RESPONSE
1), which contains a catalytic domain similar to Raf, a member of the MAP
kinase kinase kinase (MAPKKK) family
(Kieber et al., 1993). The
histidine kinase and receiver domains of ETR1 can interact with CTR1
(Clark et al., 1998;
Gao et al., 2003;
Huang et al., 2003); however,
the mechanism by which CTR1 and the ethylene receptors communicate remains to
be identified. Loss-of-function mutations in CTR1 result in
constitutive ethylene responses, indicating that CTR1 is a negative regulator
of ethylene signalling (Kieber et al.,
1993). The severity of the loss-of-function mutant phenotypes
suggests that most of the ethylene responses are mediated through CTR1. It is
presumed that CTR1 is part of a MAP kinase cascade that inhibits downstream
responses to ethylene (Fig.
6A,B). It has been proposed that CTR1 can inhibit the MAP kinase
cascade (Ouaked et al., 2003),
but this is controversial (Ecker,
2004). Further downstream in the ethylene signalling pathway is a
membrane-localised protein, EIN2, which acts as a positive regulator of
ethylene signalling (Alonso et al.,
1999). Downstream from EIN2 is EIN3, which is a key transcription
factor that mediates responses to ethylene
(Chao et al., 1997). In the
absence of ethylene, EIN3 is ubiquitinated by the SCFEBF1/2
complex, which targets it for degradation by the 26S proteasome
(Fig. 6A)
(Guo and Ecker, 2003;
Potuschak et al., 2003). In
the presence of ethylene, signalling through EIN2 prevents EIN3 from being
ubiquitinated by SCFEBF1/2, leading to EIN3 accumulation and to the
activation of ethylene-response gene expression
(Fig. 6B)
(Guo and Ecker, 2003;
Potuschak et al., 2003).
| Box 3. Two-component signalling
Signalling via the transfer of a phosphoryl group from a conserved
histidine (His) residue of a histidine kinase domain to a conserved aspartate
(Asp) residue of a receiver domain is called the two-component system
(Klumpp and Krieglstein,
2002
|
|
The cytokinin phytohormones are adenine derivatives, and they were
identified in the 1950s as compounds that, together with auxin, promote cell
division and de novo shoot formation in tobacco tissue culture. Later on, they
were shown to induce chloroplast development, promote seed germination,
release buds from apical dominance, stimulate leaf expansion, delay senescence
and regulate vascular development in several plant species
(Buchanan et al., 2000;
Mahonen et al., 2006). During
the past few years, it has become evident that cytokinins are perceived in
Arabidopsis by three related receptor histidine kinases,
CRE1/WOL/AHK4, AHK3 and AHK2 (Higuchi et
al., 2004; Inoue et al.,
2001; Nishimura et al.,
2004; Riefler et al.,
2006; Suzuki et al.,
2001; Ueguchi et al.,
2001b).
The loss-of-function mutant, cytokinin response1 (cre1)
was isolated from a screen for mutants with impaired cytokinin responsiveness
in tissue culture by Tatsuo Kakimoto's laboratory
(Inoue et al., 2001). Mapping
and complementation analysis revealed that CRE1 encodes a putative
histidine kinase (Inoue et al.,
2001), which is identical to WOODEN LEG (WOL) and to ARABIDOPSIS
HISTIDINE KINASE4 (AHK4) (Mahonen et al.,
2000; Ueguchi et al.,
2001b). CRE1 belongs to a protein family that contains three
highly homologous hybrid sensor histidine kinases: AHK2, AHK3 and
CRE1/WOL/AHK4 (Mahonen et al.,
2000; Ueguchi et al.,
2001a). The histidine kinase and receiver domains of these
CRE-family receptors are similar to the respective domains in the ethylene
receptors. Unlike many ethylene receptors, all three CRE-family receptors
contain the conserved amino acid residues required for the function of the
histidine kinase and the receiver domains, as well as a highly homologous
extracellular domain in the N-terminal region
(Fig. 3C). This N-terminal
region resembles the ligand-binding domain that is found in diverse receptors
of prokaryotes, plants and the amoeba Dictyostelium discoideum. It is
called the Cyclase/Histidine kinase-Associated Sensing Extracellular (CHASE)
domain, and is bound by a diverse set of low molecular weight ligands
(Anantharaman and Aravind,
2001; Mougel and Zhulin,
2001). Three laboratories have independently demonstrated that
CRE1/WOL/AHK4 (hereafter referred to as CRE1) is a cytokinin receptor, by
carrying out assays in which yeast and bacterial histidine kinase mutants were
complemented by CRE1 in a cytokinin-dependent manner
(Inoue et al., 2001;
Suzuki et al., 2001;
Ueguchi et al., 2001b). Two
other family members, AHK2 and AHK3, also exhibit similar cytokinin-dependent
activity (M. Higuchi and T. Kakimoto, personal communication)
(Yamada et al., 2001). The
binding of cytokinin to CRE1 was demonstrated by using isolated yeast
membranes that express CRE1 (Yamada et
al., 2001). The wol allele of CRE1 exhibits cytokinin
insensitivity due to a single nucleotide mutation in the CHASE domain
(Mahonen et al., 2000)
(A.P.M., M. Higuchi, Y.H. and T. Kakimoto, unpublished). This mutation
abolishes the binding of cytokinins in yeast, indicating that the CHASE domain
senses cytokinins (Yamada et al.,
2001). In vitro, CRE1 has been shown to phosphorylate the
conserved His residues of downstream components called the ARABIDOPSIS
HISTIDINE PHOSPHOTRANSFER PROTEINS (AHPs) in a cytokinin-dependent manner,
demonstrating that, following cytokinin binding, CRE1 initiates phosphorelay
(Fig. 6C) (M. Higuchi and T.
Kakimoto, personal communication). From AHPs, the phosphoryl group is believed
to be transferred to the conserved Asp residue within a receiver domain of
type-B ARABIDOPSIS RESPONSE REGULATORS (ARRs), which act as transcription
factors (Fig. 6C)
(Hwang and Sheen, 2001;
Sakai et al., 2000;
Sakai et al., 2001). Type-B
ARRs activate the transcription of cytokinin primary response genes, including
type-A ARRs (Brandstatter and Kieber,
1998; Hwang and Sheen,
2001; Rashotte et al.,
2003; Sakai et al.,
2001; Taniguchi et al.,
1998).
Recently, the analysis of Arabidopsis plants carrying single,
double and triple mutations of the cytokinin receptors has demonstrated that
the CRE-family receptors are positive regulators of cytokinin signalling
(Higuchi et al., 2004;
Nishimura et al., 2004;
Riefler et al., 2006). The
triple mutants do not respond to cytokinins in various physiological assays
nor induce cytokinin primary-response genes, suggesting that the CRE-family
members are the only cytokinin receptors in Arabidopsis. These triple
mutants are small, mainly as a result of reduced cell proliferation in the
shoot and the root apical meristems, yet they possess all of the basic organs
(Fig. 5C). Therefore, either
cytokinins are not required for the formation of a basic plant body plan, or,
alternatively, there may still be another type of cytokinin receptor that is
required during embryogenesis. Various physiological and molecular analyses,
as well as expression studies, have revealed that these three receptors have
overlapping, yet distinct, roles in cytokinin signalling that mediate various
developmental and physiological processes
(Higuchi et al., 2004;
Nishimura et al., 2004;
Riefler et al., 2006).
Plant vascular tissue consists of three tissue types: the transporting
tissues, xylem and phloem; and the meristematic tissue, procambium (or
cambium), from which the transporting tissues originate. Both the CRE-family
triple mutants and the wol mutant contain fewer vascular cell
lineages in the root, and all of these lineages differentiate as protoxylem,
an early differentiating xylem cell type
(Fig. 5D)
(Mahonen et al., 2006;
Scheres et al., 1995). A
similar, all-protoxylem, phenotype is observed in transgenic lines when
cytokinin is degraded from the root vascular bundle. Ectopic protoxylem
appears soon after the induction of a cytokinin-depleting enzyme called
CYTOKININ OXIDASE 1, indicating that cytokinin signalling primarily inhibits
protoxylem specification and promotes procambial cell identity
(Mahonen et al., 2006).
Further analysis of the wol mutation has indicated that in the
absence of cytokinin, CRE1 preferentially dephosphorylates AHPs, indicating
that phosphorelay in plants can be bidirectional (M. Higuchi and T. Kakimoto,
personal communication).
A gain-of-function mutation in AHK3 results in delayed senescence,
whereas a loss-of-function mutant exhibits reduced sensitivity for
cytokinin-mediated inhibition of leaf senescence
(Kim et al., 2006). Because
AHK3, but not the other two cytokinin receptors, affect this process,
these data indicate that the long-known effect of cytokinin on delaying
senescence operates specifically through AHK3
(Kim et al., 2006).
Abscisic acid and post-transcriptional RNA processing
Abscisic acid (ABA) was identified by two groups independently in the 1960s
as a compound that promotes the shedding of cotton fruit and induces dormancy
in sycamore seeds, but since then it has been studied more in the context of
adaptation to environmental stress
(Buchanan et al., 2000).
However, the recent discovery that an ABA receptor is a key regulator of the
transition between vegetative and reproductive growth established a clear link
between ABA and plant development (Razem
et al., 2006). Unlike the other receptors discussed so far, which
were identified as components of the relevant signalling pathways through
genetic screens, the ABA receptor was discovered using a biochemical approach.
By screening a translated barley cDNA library for proteins that bound to ABA
in vitro, Robert Hill's laboratory identified the ABAP1 protein
(Razem et al., 2004). ABAP1 is
a hydrophobic molecule that has a tryptophan-tryptophan (WW) interaction
domain similar to that in the Arabidopsis floral repressor FCA. FCA
was subsequently shown to bind ABA in in vitro co-immunoprecipitation assays
(Razem et al., 2006).
FCA was originally discovered through a genetic screen for
late-flowering Arabidopsis mutants
(Koornneef et al., 1991).
Loss-of-function fca mutants flower substantially later than
wild-type Arabidopsis under most conditions
(Fig. 5E), whereas
overexpression of FCA leads to an early-flowering phenotype
(Macknight et al., 1997). FCA
is a member of the autonomous group of floral regulators that exert an
internal developmental control over flowering. Like other autonomous
components, delayed flowering in fca is caused directly by elevated
levels of FLC mRNA (Michaels and
Amasino, 2001; Sheldon et al.,
2000). FLC is a MADS box transcription factor that inhibits
flowering by negatively regulating the expression of the flowering pathway
integrator genes SOC1 and FT
(Michaels and Amasino, 1999;
Samach et al., 2000). FCA
activity requires the presence of a second autonomous pathway protein, FY,
which contains an RNA 3'-end processing factor
(Simpson et al., 2003). The
two proteins interact through the WW domain of FCA to regulate gene expression
post-transcriptionally by promoting the premature cleavage and polyadenylation
of target precursor mRNA (pre-mRNA), at least in the context of the
autoregulation of FCA (Macknight
et al., 2002; Quesada et al.,
2003). However, in the presence of ABA, this interaction between
FCA and FY proteins is severely inhibited in in vitro pull-down assays
(Razem et al., 2006), although
it remains to be investigated whether ABA disrupts the FCA-FY interaction in
vivo (Fig. 7). The significance
of this ABA-mediated inhibition was demonstrated in a study in which plants
treated with ABA phenocopied fca and fy mutants; they were
late flowering, had accumulated levels of FLC mRNA and failed to
autoregulate FCA by cleavage of its own pre-mRNA
(Macknight et al., 2002;
Quesada et al., 2003;
Razem et al., 2006). An
earlier report had also suggested a link between ABA signalling, FLC
regulation and the control of flowering
(Bezerra et al., 2004).
|
). Additionally, mutations in ABA downstream response genes
that affect stomatal opening, such as in ABI1 and ABI2
(Chak et al., 2000), do not
show impaired ABA responsiveness in terms of delayed flowering and cleavage of
FCA pre-mRNA (Razem et al.,
2006), indicating that not only do additional ABA receptor(s)
exist, but also possibly distinct signalling pathways. Convergence of hormonal signals downstream of receptors
So far we have discussed the phytohormone receptors and their related
signal transduction pathways individually. However, there is substantial
evidence that these regulatory pathways interact to control plant development.
These interactions can occur at multiple levels, for example, by controlling
the biosynthesis of other hormones or the expression of components in other
signal transduction pathways. Another emerging theme is that of crosstalk at
the level of signal transduction intermediates directly downstream of
receptors. Recently, Nemhauser et al.
(Nemhauser et al., 2004) and
Goda et al. (Goda et al.,
2004) have provided evidence that brassinosteroid and auxin
signalling converge at the level of transcriptional regulation in regulating
hypocotyl elongation in Arabidopsis. There seems to be a subset of
genes that contain regulatory elements that are commonly regulated by the two
hormones. Nemhauser et al. suggest that the activity of some of the auxin
signalling transcription factors, ARFs, is modulated by the formation of
specific transcriptional complexes, involving input from both auxin and
brassinosteroid signalling pathways. Furthermore, Nakamura et al. provided
evidence that the activity of certain Aux/IAA proteins could be jointly
regulated by auxin and brassinosteroids
(Nakamura et al., 2006).
Analogously, Fu and Harberd have provided evidence that auxin modulates
gibberellin response in controlling root elongation
(Fu and Harberd, 2003). They
indicate that proper auxin signalling is required for GA-induced proteolysis
of the DELLA growth repressing proteins, although the exact mode of this
remains to be investigated.
There is also genetic evidence that signals from the GA and autonomous
pathways (including ABA) may integrate at the promoter of SOC1
(Moon et al., 2003). Reduced
abundance of FLC mRNA (e.g. by low levels of ABA) alone is
insufficient to activate SOC1, and requires additional positive
factors. Under short-day conditions, gibberellin signalling could provide such
factors, as GA-biosynthetic and GA-signalling mutants flower extremely late;
this correlates with reduced SOC1 expression. The exact mode of this
convergence remains to be identified.
All three cytokinin receptors and some ethylene receptors contain the
conserved residues that are required for histidine kinase activity, and for
phosphorelay via the receiver domain (Fig.
3B,C). Therefore, both cytokinin and ethylene receptors have the
potential to phosphorylate or dephosphorylate the same downstream components,
the AHPs, enabling crosstalk between these two signalling pathways
(Fig. 6). This potential
convergence could occur at the AHPs, as specificity between the AHPs and
various Arabidopsis histidine kinases does not seem to be strict
(Tanaka et al., 2004;
Urao et al., 2000). However,
no compelling evidence to support this hypothesis has been presented.
Concluding remarks
Although considerable progress has recently been made in understanding hormone perception in plants, we are just beginning to comprehend the whole picture of developmental control following phytohormone perception. Receptors for all of the known hormones regulating plant development have been identified; however, for some phytohormones, such as abscisic acid, additional receptor(s) remain to be discovered. Considering the number of receptor kinases, RNA binding proteins and F-box proteins in plants, it is possible that some of them might act as receptors for other phytohormones, potentially including ones not yet identified. Also, there are still many interesting biochemical aspects of hormone receptors yet to be uncovered, such as substrate specificity in the case of multiple gibberellin, brassinosteroid and cytokinin ligands, multimerization, and the desensitization of a signal following ligand binding.
Similarly, our understanding of the signalling pathways downstream of the receptors remains preliminary. In each signalling pathway, there are still multiple gaps in our knowledge, especially concerning the specificity of certain hormone responses in a given developmental context, i.e. how a certain response is regulated spatially and temporally in individual species. New high-throughput gene expression analysis techniques and system-wide approaches will be important in investigating these questions.
ACKNOWLEDGMENTS
We thank Tatsuo Kakimoto, Stefan Kepinski, Pia Runeberg-Roos, Jaakko Kangasjärvi and Daniel Schubert for critical comments on the manuscript; Sunethra Dharmasiri, Dolf Weijers, Mark Estelle and Makoto Matsuoka for providing images; and Tinde Päivärinta for graphical assistance. The authors are supported by the Academy of Finland, Tekes, University of Helsinki and ESF.
Footnotes
* These authors contributed equally to this work 
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Asp
