Current Biology 21, R338–R345, May 10, 2011 ª2011 Elsevier Ltd All rights reserved
036
The Molecular Mechanism and Evolution of the
GA–GID1–DELLA Signaling Module in Plants
Tai-ping Sun
Bioactive gibberellins (GAs) are diterpene phytohormones
that modulate growth and development throughout the
whole life cycle of the flowering plant. Impressive
advances have been made in elucidating the GA pathway
with the cloning and characterization of genes encoding
most GA biosynthesis and catabolism enzymes, GA recep-
tors (GIBBERELLIN INSENSITIVE DWARF1, GID1) and early
GA signaling components. Recent biochemical, genetic
and structural analyses demonstrate that GA de-represses
its signaling pathway by GID1-induced degradation of
DELLA proteins, which are master growth repressors, via
a ubiquitin–proteasome pathway. Multiple endogenous
signals and environmental cues also interact with the
GA–GID1–DELLA regulatory module by affecting the ex-
pression of GA metabolism genes, and hence GA content
and DELLA levels. Importantly, DELLA integrates different
signaling activities by direct protein–protein interaction
with multiple key regulatory proteins from other pathways.
Comparative studies suggest that the functional
GA–GID1–DELLA module is highly conserved among
vascular plants, but not in the bryophytes. Interestingly,
differentiation of the moss Physcomitrella patens is regu-
lated by as yet unidentified ent-kaurene-derived diter-
penes, which are distinct from the common active GAs in
vascular plants.
Introduction
The role of gibberellins (GAs) in promoting stem growth in
seed plants, angioperms and gymnosperms was first
discovered by studies of the Bakanae (foolish seedling)
disease in rice [1]. Gibberella fujikuroi, a pathogenic fungus,
produces GAs that cause excessive elongation of the in-
fected rice plants. Since the determination of the chemical
structures of the fungal produced GAs in the 1950s, over
130 GAs have been identified in vascular plants, as well as
in fungi and bacteria ([2]; http://www.plant-hormones.info/
ga1info.htm). However, very few GAs are active growth
regulators in seed plants (Figure 1A), with the majority being
biosynthetic intermediates or catabolites of bioactive GAs.
Studies of dwarf mutants, analysis of GA content in wild-
type and mutant plants, and treatment with GAs revealed
that bioactive GAs are endogenous phytohormones that
modulate diverse developmental processes in seed plants
[3–5]. GA promotes seed germination and vegetative
growth. In some species, GA also induces flower initiation
and regulates flower, fruit and seed development. GA
research has had major impacts on agriculture. The most
notable example is the development of the high-yielding
semi-dwarf rice and wheat varieties, which fueled the
success of the ‘Green Revolution’ in the 1960s [6]. The
dwarfing traits in these crops were caused by alterations
Department of Biology, Duke University, Durham, NC 27705, USA.
E-mail: tps@duke.edu
DOI 10.1016/j.cub.2011.02.
Review
in GA biosynthesis [7] or in the GA response [8]. In addition,
commercial applications of GAs are routine agriculture
practices, for example to increase malting of barley during
beer production and to enlarge fruit size of seedless grapes.
GA inhibitors are also applied to retard the stature of nursery
plants. In the past two decades, the GA biosynthesis and
catabolism pathways in angiosperms have been elucidated
at the molecular level [3,9,10]. Significant progress has also
been made in GA perception and the early signaling
pathway in angiosperms (flowering plants). Several recent
reviews have discussed the GA receptor and its signaling
pathway in detail [11–14]. This review will highlight new
insights into the molecular mechanism of GA perception
and signaling in angiosperms. In addition, I will also discuss
the evolutionary aspect of GA function, which has been
delineated by the recent studies on the GA pathways in early
land plants [15,16].
GA Biosynthesis and Deactivation Pathways
in Angiosperms
GA biosynthesis and catabolism pathways in angiosperms
have been well characterized (Figure 1C), and several recent
reviews have described this topic in detail [3,9,10]. Geranyl-
geranyl diphosphate (GGDP) is the common precursor for
GAs. GGDP is first converted to ent-kaurene, the first
committed intermediate in the GA pathway, in a two-step
cyclization reaction, catalyzed by ent-copalyl diphosphate
synthase (CPS) and ent-kaurene synthase (KS). ent-Kaurene
then undergoes stepwise oxidation followed by ring contrac-
tion, catalyzed by ent-kaurene oxidase (KO) and ent-kaure-
noic acid oxidase (KAO), to produce GA12 (a non-13-hydrox-
ylated GA). GA12 can be further converted to GA53 by
13-hydroxylation. GA12 and GA53 are then converted to
various GA intermediates and bioactive GAs, including GA4
and GA1, by two parallel pathways that include a series of
oxidation steps catalyzed by 2-oxoglutarate-dependent di-
oxygenases (2ODDs), GA 20-oxidases (GA20ox) and GA
3-oxidases (GA3ox) (Figure 1C). The common features of
the four major active GAs — GA1, GA3, GA4 and GA7 — in
seed plants are a 3b-hydroxyl group, a carboxyl group on
C-6, and a lactone between C-4 and C-10 on ring A (Fig-
ure 1A). 2b-Hydroxylation, which is catalyzed by another
subgroup of 2ODDs, GA 2-oxidases (GA2ox) (Figure 1C), is
the major reaction to convert active GAs (and/or their precur-
sors) to inactive forms. Two additional GA-deactivation
mechanisms are epoxidation of non-13-hydroxylated GAs
in rice [17] and methylation of GAs in Arabidopsis [18]. Future
studies will be needed to determine whether and how these
two new types of modification are widely used in different
species to modulate active GA content. The GA biosynthesis
and catabolism genes encoding 2ODDs that act in the late
stages of the GA pathway play a key role in modulating
bioactive GA levels through a feedback mechanism [3,9].
Inhibition of GA signaling activity, by treatment with GA
biosynthesis inhibitors or by genetic mutations, causes up-
regulation of some of the GA biosynthesis genes (GA20ox
and GA3ox) and downregulation of GA catabolism genes
(GA2ox). This feedback mechanism plays a central role in
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Figure 1. GA biosynthesis and deactivation A Bioactive GAs (angiosperms) B Antheridiogen

pathways in plants. (ferns)
(A) Bioactive GAs in seed plants. GA3 is the O O O OH O OH O
most abundant active GA made in fungi. GA4
OC H OC H OC H OC H OC H
is the major active GA in Arabidopsis. The HO HO HO
HO H H H H H
common features of active GAs are high- CO2H CO2H CO2H CO2H CO2CH3
lighted in red in GA4. (B) GA9 methylester GA4 GA7 GA1 GA3 GA9-methylester
and several other GA methylesters (not
shown) are antheridiogens in ferns. (C) GA Non-13-OH GAs 13-OH GAs
biosynthesis pathway from GGDP, and GA
deactivation by GA2ox. The solid arrow indi- C
cates a single-step reaction. The unfilled
arrow indicates a multiple-step reaction. OPP OPP
H
H H H
GGDP, geranylgeranyl diphosphate; CDP, H
CPS KS H KO H KAO
ent-copalyl diphosphate; CPS, ent-copalyl H CHO
CO2H CO2H
diphosphate synthase; KS, ent-kaurene GGDP CDP ent-kaurene ent-kaurenoic acid GA12-aldehyde
synthase; KO, ent-kaurene oxidase; KAO,
KAO
ent-kaurenoic acid oxidase; GA13ox, GA
13-oxidase; GA20ox, GA 20-oxidase; GA3ox, Non-13-OH
O O O
GA 3-oxidase; GA2ox, GA 2-oxidase. The pathway HO
active GAs are labeled in red, GA biosynthesis H OC H OC H OC H
H CO H GA15 GA24
enzymes are labeled in purple, and the deac- H HO H HO H
CO2H
2 CO2H CO2H CO2H
tivation enzyme is labeled in orange.
GA12 GA9 GA4 GA34
GA13ox
GA20ox GA3ox GA2ox
OH O OH O OH O
13-OH HO OH
maintaining GA homeostasis and will pathway H OC H OC H OC H
H CO H GA44 GA19
be discussed again in the later section 2
H
CO2H
HO H
CO2H
HO H
CO2H
CO2H
on GA signaling.
GA53 GA20 GA1 GA8

GA Biosynthesis Pathways in Fungi Current Biology

and Early Land Plants
Like angiosperms, fungi (such as
G. fujikuroi and Phaeosphaeria) also
produce GAs. However, the GA biosynthetic pathway in
fungi is markedly different from that in angiosperms (see
[19] for extensive review). The conversion of GGDP to en-
t-kaurene in fungi is catalyzed by a single bifunctional
terpene cyclase [20,21], instead of the two separate enzymes
CPS and KS. The sequence of the fungal KAO (a P-450
enzyme) has little similarity to the KAOs of angiosperms.
Moreover, the fungal pathway downstream from GA12-alde-
hyde is distinct from that in angiosperms and only utilizes
P-450 enzymes (in contrast to the 2ODDs in angiosperms).
These findings suggest that GA biosynthetic pathways in
fungi and angiosperms have evolved independently. For
a long time it was unclear why some fungi produce GAs
because strains that are defective in GA biosynthesis grow
normally in culture [19]. However, a recent study suggests
that GA promotes infection by necrotrophic pathogens
(such as G. fujikuroi) as a result of suppressing the jasmonic
acid signaling pathway [22].
Comparative genomic studies have helped to deduce the
origin of phytohormones. Auxin, cytokinin and abscisic
acid pathways are present in Physcomitrella patens, a
moss that is a model system for bryophytes, but are absent
in the unicellular green algae Chlamydomonas reinhardtii,
suggesting the important roles of these phytohormones in
regulating multicellular development and the dehydration
stress responses of early land plants [23,24]. However, the
story of GA is not as straightforward. In P. patens, although
ent-kaurene and ent-kaurenoic acid are produced, none of
the common GAs is detected [25]. P. patens contains a single
bifunctional diterpene cyclase PpCPS/KS gene [26], similar
to the fungal system [21]. The knockout cps/ks mutant lacks
ent-kaurene and is defective in the differentiation of proto-
nema, the filamentous stage of the haploid gametophyte in
bryophytes [25]. Germination of spores in P. patens
produces filamentous protonemal cells that contain many
chloroplasts and are known as chloronemata. Some of the
wild-type chloronemata will give rise to caulonemata that
are faster growing and can produce gametophores.
However, the cps/ks mutant is defective in the
chloronemata-to-caulonemata transition. This develop-
mental defect of the cps/ks mutant can be rescued by
application of ent-kaurene or ent-kaurenoic acid. In contrast,
the bioactive GAs in angiosperms — GA3 and GA4 — do not
induce protonema differentiation. Intriguingly, GA9-methyl-
ester (Figure 1B), an inactive GA in angiosperms but a phero-
mone (antheridiogen) in ferns, can promote protonema
differentiation in the cps/ks mutant. However, GA9-methyl-
ester is w10-fold less efficient in rescuing the defects of
the cps/ks mutant than ent-kaurenoic acid. These observa-
tions suggest that unknown diterpene(s) derived from kaure-
noic acid control protonema differentiation in P. patens.
Identification of the active compound(s) and studies on
additional bryophytes, such as other mosses, hornworts
and liverworts, will reveal whether this is a common mecha-
nism in bryophytes.
Studies on bryophytes indicate that biosynthesis of active
GAs in angiosperms had evolved after the bryophyte diver-
gence. Lycophytes are the oldest group of the living vascular
land plants [27]. In the model lycophyte Selaginella
moellendorffii, the bioactive GA4 and a precursor GA24 —
both non-13 hydroxylated GAs (Figure 1) — are present,
but the 13-hydroxylated GA GA1 is undetectable [15]. In addi-
tion, S. moellendorffii contains GA20ox and GA3ox genes
that encode enzymes with similar properties as those in
angiosperms. These results indicate that S. moellendorffii
has a functional GA biosynthesis pathway that is similar to
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the non-13 hydroxylation pathway in angiosperms (Fig-
ure 1C). However, the role of GA in S. moellendorffii is unclear
because treatment with 1025 M GA4 does not have signifi-
cant effects on its stem/leaf growth [15]. Interestingly, treat-
ment with 1026 M uniconazole, which blocks ent-kaurene
oxidase activity, reduces stem length by w30%. Again,
GA4 cannot rescue this dwarfing effect of uniconazole, indi-
cating that ent-kaurene-derived compound(s), but not GA4,
are important growth regulator(s) in this lycophyte. In ferns,
the GA methylesters are antheridiogens that control the
sex of the gametophyte [28]. However, these GA methylest-
ers are not active GAs in angiosperms, and there is no known
effect of GA on sporophyte growth in ferns.
The GA–GID1–DELLA Signaling Module in Angiosperms
The GA receptor GIBBERELLIN INSENSITIVE DWARF1
(GID1) was first identified by studies of GA-insensitive dwarf
rice mutants [29]. Arabidopsis contains three GID1 orthologs
(GID1A, GID1B and GID1C) [30], which have some overlap-
ping but also distinct functions in regulating different devel-
opmental processes [31–34]. In vitro binding assays showed
that OsGID1s and AtGID1s are soluble GA receptors, which
bind with high affinity only to bioactive GAs, but not to inac-
tive GA derivatives [29,30]. The carboxy-terminal core
domain of GID1 is highly similar to the plant carboxylesterase
family of the a/b-hydrolase fold superfamily [35,36].
However, a conserved histidine residue near the carboxyl
terminus that is essential for esterase catalytic function is
absent [29]. The GID1 subfamily members also contain
a unique amino-terminal extension [35,36] (see below).
GID1–GFP fusion proteins localized to both the cytoplasm
and the nucleus in transgenic plants [29,33].
Upon GA binding, how does GID1 activate the downstream
signaling pathway? Accumulating evidence indicates that the
GA–GID1 complex triggers rapid degradation of the master
growth repressors, the DELLA proteins (reviewed in [14,37];
also see below). DELLAs are nuclear transcriptional regula-
tors that repress GA signaling and restrict plant growth,
presumably by causing transcriptional reprogramming.
DELLAs were initially identified by studies of the
Arabidopsis GA-response mutants rga (for repressor of
ga1-3) and gai (for GA-insensitive) [38,39]. Functional DELLA
orthologs have been identified in many angiosperms (re-
viewed in [40]). DELLAs belong to a subfamily of the plant-
specific GRAS, for GAI, RGA and SCARECROW (SCR), family
of regulatory proteins [41,42]. DELLA, like all GRAS family
members, contains a conserved carboxy-terminal GRAS
domain that confers transcriptional regulator function. In its
amino terminus, DELLA has a unique DELLA domain that is
required for GA-induced degradation [43,44]. Arabidopsis
contains 5 DELLAs — RGA, GAI, RGA-LIKE1 (RGL1), RGL2
and RGL3 — which display overlapping but also some
distinct functions in repressing GA responses [45–49], sug-
gesting that multiple DELLAs may provide more dynamic
control of GA-mediated growth throughout plant develop-
ment. In contrast, monocots, such as rice and barley, only
contain a single DELLA gene — SLENDER1 (SLR1) in rice
and SLENDER in barley [50–52]. Interestingly, the rice
genome contains two SLR1-LIKE (SLRL) genes encoding
proteins that lack the DELLA domain and are therefore
GA-resistant [53]. Overexpression of SLRL in transgenic
rice inhibits shoot growth, although its effect is weaker than
overexpression of SLR1. The unique GA-resistant property
of SLRL may play a critical role in submergence tolerance
of the lowland rice [54]. To survive flash flooding, the submer-
gence-tolerant rice varieties stop shoot elongation tempo-
rarily to conserve energy. This growth inhibition response is
due to a reduction in GA responses after submergence, which
is achieved by increased transcription of SLR1 and SLRL1 by
SUBMERGENCE-1A (SUB1A, an ethylene-responsive-factor
(ERF) transcription factor) [54]. The GA-resistant SLRL1
protein may be crucial to sustain the growth inhibition during
submergence conditions because reduced GA responses
increase GA levels and hence promote SLR1 degradation.
As mentioned, the GA signal induces rapid proteolysis of
its signaling repressor DELLA [55]. What is the molecular
mechanism involved? Protein and mutant studies indicated
that both GID1 and a specific F-box protein — SLEEPY1
(SLY1) in Arabidopsis, and GIBBERELLIN INSENSITIVE
DWARF2 (GID2) in rice — are required for DELLA protein
degradation [29,31,56,57]. The amino-terminal DELLA
domain is essential for GA-induced degradation to occur
[44], although this domain does not interact with the F-box
protein [58]. It turns out that GID1 directly binds to the
conserved DELLA, LEXLE and VHYNP motifs within the
amino-terminal domain of DELLA proteins in a GA-depen-
dent manner. The first evidence of this mechanism came
from yeast two-hybrid and in vitro pull-down assays [29,31],
followed by the recent determination of the structure of the
GA–GID1–DELLA complex by X-ray crystallography [35].
The crystal structure of the GA–GID1–DELLA complex
contains the active GA (GA3 or GA4), AtGID1A and the DELLA
domain of the AtDELLA GAI. At the same time, the crystal
structure of GA–OsGID1 was also solved [36]. These struc-
tural studies reveal that GID1 contains a carboxy-terminal
core domain that forms a GA-binding pocket, and an
amino-terminal extension domain (N-Ex) that acts as a lid
for the pocket (Figure 2A–C). Without GA binding, the N-Ex
of GID1 has a flexible structure that is highly sensitive to
protease treatment. Binding of GA to the carboxy-terminal
core domain of GID1 induces a conformational switch of its
N-Ex to cover the GA-binding pocket (like closing a lid), and
also creates hydrophobic DELLA-binding surfaces
(Figure 2A–C). Although there is no direct contact between
DELLA and GA, DELLA binding further stabilizes the
GA–GID1–DELLA complex. These studies indicate that
bioactive GA is an allosteric inducer of its receptor GID1.
This is different from the mechanism of auxin perception in
which auxin functions as a ‘molecular glue’ that brings the
F-box protein (TIR1 and its homologs) and its substrate
protein (IAA/AUX family proteins) together without altering
the conformations of these proteins [59].
Upon GA induction, DELLA is recruited to the SCFSLY1/GID2
ubiquitin E3 ligase complex for poly-ubiquitination and
subsequent degradation by the 26S proteasome [52,56,58].
What happens after GA–GID1 binds to DELLA in order to
trigger enhanced recognition of DELLA by the F-box protein
SLY1/GID2? Yeast two-hybrid assays show that SLY1 inter-
acts weakly with the GRAS domain of the DELLA protein [58].
This is consistent with the observation that carboxy-terminal
truncation or a missense mutation in the VHIID region within
the GRAS domain stabilizes the mutant DELLA protein
[58,60]. Yeast three-hybrid assays further demonstrate that
RGA–SLY1 interaction is enhanced in the presence of GID1
and GA. Based on these observations, it was proposed
that DELLA–GID1 interaction leads to conformational
changes in the rest of the DELLA protein to enhance recog-
nition of its GRAS domain by the F-box protein, which
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Figure 2. The GA–GID1–DELLA complex.
A B
(A,B) Crystal structure of the complex that
contains GA3, AtGID1A and the DELLA
domain of GAI (an AtDELLA). (A) The molec-
ular surface of the complex. (B) Ribbon repre-
sentation. The carboxy-terminal GID1 core
domain is labeled in blue, the GID1 amino-
terminal extension (N-Ex) is in cyan, and the
DELLA domain is in pink. The bound GA3 is
represented as a space-filling model with
carbon in green and oxygen in red. (C) A
model for the GA-dependent GID1–DELLA
interaction and subsequent SCFSLY1 binding.
GA binding first induces a conformational
change in the N-Ex of GID1 for DELLA C
binding, which promotes binding of the
GRAS domain of the DELLA protein to GID1.
N-Ex
This stable complex enables efficient SCFSLY1
recognition and subsequent degradation of
DELLA by the proteasome. This figure was
modified from Murase et al. [35]. GID1
promotes polyubiquitination by SCFSLY1/GID2. This model
was further refined by a recent study [61] showing that the
GRAS domain of the rice DELLA (SLR1) also interacts with
GID1 to stabilize this protein complex, but this interaction
only occurs after the amino-terminal DELLA/VHYNP region
has bound to GID1. A dominant slr1-d4 mutant was found
to contain a G576V substitution in the GRAS domain, which
confers increased stability to the SLR1 protein. Importantly,
yeast two-hybrid and surface plasmon resonance assays
reveal that slr1-d4 not only fails to bind the F-box protein
GID2, but also displays a much weaker interaction with
GID1. These results suggest that sequential binding of the
DELLA and then GRAS domains of the DELLA protein to
GID1 leads to a stable DELLA–GID1 complex, which allows
efficient recognition by the F-box protein [61] (Figure 2C).
This model is supported by another study showing that
GID1 and DELLA are co-immunopreciptated with SLY1
from protein extracts prepared from transgenic Arabidopsis
overexpressing both FLAG-tagged SLY1 and HA-tagged
GID1 [62]. Future structural studies on the full-length DELLA
protein and the F-box protein will be needed to verify the
current model.
The sequence of one of the Arabidopsis GID1s, AtGID1B,
is more divergent than that of the other two AtGID1s and of
OsGID1 [30]. Interestingly, AtGID1B displays a unique prop-
erty, as it can bind to DELLAs in a GA-independent manner in
yeast two-hybrid assays [30]. A recent study reveals that
a loop region in OsGID1 plays a critical role in the GA-depen-
dent interaction of GID1 with DELLA [63]. P99S or P99A
substitution within this loop allows OsGID1 to bind DELLA
independent of GA. Interestingly, among the three AtGID1s,
only AtGID1B does not contain a proline residue in this loop
region. Interaction kinetic studies show that the dissociation
constants and the affinity constants of GA-independent
GID1s (OsGID1P99A and AtGID1B) for GA are about 10–20-
fold lower than those of GA-dependent GID1s (wild-type
OsGID1 and AtGID1A). Therefore, OsGID1P99A and
AtGID1B are also hypersensitive to GA. Their model
suggests that the GA-independent binding of OsGID1P99A
and AtGID1B to DELLA is caused by an altered conformation
DE
DELLA DELLA
G
GID1A GID1A
N
N-Ex GA3 N-Ex
G
GID1A GID1A
C
Core Core
GA DELLAs
GRAS DELLA DELLA SCFSLY1
N SCFSLY1
Water DELLA
GRA
GRA
S
GID1 GID1 GID1
Current Biology
of the N-Ex so that it resembles a partially closed lid even
without GA binding [63]. Importantly, AtGID1B-like GA
receptors are also present in soybean (Glycine max) and
Brassica napus, leading to the hypothesis that GA-indepen-
dent and GA-hypersensitive GID1s may play a unique role in
the response to specific developmental or environmental
conditions. Domain-swapping experiments indicate that
the loop region, but not the proline residue, determines the
GA-independent property of soybean GID1s.
In addition to GA-dependent proteolysis, recent studies
suggest that DELLA activity may be modulated by additional
mechanisms. Overexpression of GID1 rescues the dwarf
phenotype of the sly1 and gid2 mutants without reducing
DELLA levels, suggesting that GID1–DELLA interaction can
inhibit DELLA function without protein degradation [64,65].
This is consistent with the observation that GID1 can directly
interact with the GRAS domain of DELLA [61], which is
involved in transcriptional regulation of target genes. Post-
translational modifications including O-GlcNAcylation by
SPINDLY and phosphorylation by a casein kinase may also
affect DELLA activity [66–68]. However, direct evidence for
O-GlcNAcylation of DELLA and the effects of O-GlcNAcyla-
tion and phosphorylation on DELLA function will require
further investigation.
Presence of Functional GA–GID1–DELLA Signaling
Module in Lycophytes, But Likely Absence in Bryophytes
The moss P. patens contains two GID1-Like and two DELLA-
Like genes [15,16,69]. However, PpGID1s do not display
GA-binding activity in vitro or interact with PpDELLAs in
yeast two-hybrid assays [15,16]. In addition, the mutant lack-
ing functions of both DELLA-Like genes does not show any
growth defects [16]. These results suggest that the roles of
PpGID1s and PpDELLAs are distinct from those in
angiosperms.
Studies on S. kraussiana and S. moellendorffii indicate
that a functional GA–GID1–DELLA signaling module is
present in lycophytes [15,16]. Yeast two-hybrid assays
show that SkGID1s and SmGID1s interact with SkDELLAs
and SmDELLAs, respectively, in a GA-dependent manner.
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Figure 3. The interaction network between

Auxin Ethylene the GA–GID1–DELLA signaling module and
Cytokinin (root/stem) (root growth) other internal and external cues.
(SAM) Abiotic stresses The GA–GID1–DELLA regulatory module is
(cold, salt) highlighted in orange. Signals that promote
bioactive GA accumulation are labeled in
blue, whereas signals that reduce GA levels
Light Biotic stresses are highlighted in purple. DELLA interacts
(germination) (necrotrophic pathogens) directly with multiple regulatory proteins
GA (PIFs, SCL3, ALC and JAZs; highlighted in
(biotrophic pathogens) green) to mediate crosstalk between GA and
other signaling pathways (light and JA
signaling, and root and fruit patterning). Acti-
ABA Light vation or inhibition could be via different
(hypocotyl) modes of action: PD, protein degradation;
TC GID1 PPI, protein–protein interaction; TC, tran-
TC scription. SAM, shoot apical meristem; ABA,
PD SCFSLY1/GID2 abscisic acid; JA, jasmonic acid.
PD
PPI

TC PPI
DELLA PIF3/PIF4
XERICO transcription factors [70,71]. The
first supporting evidence for this
idea came from two studies reporting
PPI PPI PPI an interaction between DELLA
Seed ? and PHYTOCHROME INTERACTING
germination FACTORs (PIFs), belonging to
JAZs ALC SCL3 Hypocotyl
elongation subfamily 15 of bHLH transcription
factors in Arabidopsis [72,73]. The
DELLA–PIF interaction inhibits PIF-
induced hypocotyl elongation by
blocking the transcription of PIF’s
Other GA JA-mediated Valve margin Root elongation,
responses defense development seed germination target genes [72,73]. In an effort to
response elucidate how DELLA proteins regulate
Current Biology
plant growth and development, 14
putative DELLA target genes were
identified by microarray studies
using an inducible system [70]. Chro-
matin immunoprecipitation (ChIP)–
Interestingly, GA4 as well as several inactive GAs (e.g., GA9, quantitative PCR analysis confirmed that DELLA associates
GA51) in angiosperms are able to promote the SmGID1– with several promoters of its target genes. Surprisingly,
SmDELLA interaction [15]. Therefore, the ligand-binding expression of all 14 genes is upregulated by DELLA and
property of SmGID1s appears to be less selective than the downregulated by GA. Several DELLA target genes encode
GID1s in angiosperms. In addition to the GA-dependent GA biosynthesis enzymes or GA receptors, suggesting that
GID1–DELLA interaction, SmDELLAs are degraded in DELLA plays a role in maintaining GA homeostasis by feed-
response to GA4 treatment. This is consistent with the pres- back regulation of positive components in the upstream
ence of SLY1/GID2 homologs in S. moellendorffii [15,69]. GA pathway (Figure 3).
These recent studies on the moss P. patens and two Other DELLA-induced target genes encode putative tran-
Selaginella lycophytes suggest that the GA–GID1–DELLA scription factors/regulators, or RING-type ubiquitin E3
signaling module arose after the bryophyte divergence ligases. XERICO, one of the DELLA target genes encoding
[15,16,69]. However, many questions remain. For example, an E3 enzyme, promotes accumulation of abscisic acid
what is the function of GA4 and DELLA in lycophytes, given that antagonizes GA effects [70,74] (Figure 3). Therefore,
that GA4 treatment cannot rescue the uniconazole-induced DELLA may restrict GA-promoted processes by modulating
growth defect in lycophytes? Also, what are the active both GA and abscisic acid pathways. SCARECROW-LIKE 3
GA-like compounds that promote sporophyte growth in (SCL3), another DELLA-induced target gene, surprisingly
lycophytes? Similarly, what is the novel signal (presumably functions as a positive regulator of GA signaling and an
an ent-kaurene-derived diterpene) required for protonemal attenuator of DELLA proteins [75,76]. SCL3 is also a GRAS
differentiation in P. patens [25]? Once this novel signaling family member, although it does not contain the GA-respon-
compound is identified, it will be important to examine sive DELLA domain. The scl3 mutant is sensitive to the GA
whether this signal is perceived by PpGID1s and can biosynthesis inhibitor paclobutrazol in seed germination,
promote PpGID1–PpDELLA interaction in P. patens. Alterna- and hypocotyl and root elongation. Co-immunoprecipitation
tively, this signal may be recognized by a novel receptor. and transient expression assays indicate that SCL3 antago-
nizes DELLA function in modulating target gene expression
Mechanism of DELLA-Regulated Plant Growth by direct protein–protein interaction [75]. Importantly, the
Without a canonical DNA-binding domain, DELLA appears SCL3–DELLA interaction not only plays a role in controlling
to modulate gene expression by interacting with other downstream GA responses, but also is involved in
Special Issue
R343
maintaining GA homeostasis by regulating expression of
upstream GA biosynthetic genes. The upregulation of SCL3
mRNA levels by DELLA may be another part of the feedback
mechanism to maintain GA homeostasis. In the primary root,
SCL3 mRNA is mainly expressed in the endodermis [41],
which appears to be the primary site of GA-induced DELLA
degradation [77]. Expression of a stabilized DELLA mutant
protein in the endodermis (but not in other cell types) inhibits
root elongation [77]. Studies with various mutants indicate
that SCL3 plays a role in determining the timing of the root
ground tissue divisions, acting downstream of SCR and
SHORT-ROOT (SHR), both of which are GRAS proteins that
are essential for endodermis specification and stem-cell
maintenance [76,78,79]. Therefore, during root development,
the SCL3–DELLA interaction integrates GA signaling activi-
ties with the developmental program controlled by SCR
and SHR.
The promoters of DELLA targets lack any conserved
DELLA-responsive cis-elements, suggesting that DELLA
interacts with different transcription factors to regulate
target genes [70]. In addition to PIFs (bHLH proteins) and
SCL3 (a GRAS protein), DELLA has been shown recently to
interact with another class of transcription regulators, the
jasmonic acid ZIM-domain proteins (JAZs) [80] (also see
below). This further supports the notion that DELLA may
interact with multiple classes of transcription factors.
Interaction between GA and Other Signaling Pathways
Overwhelming evidence accumulated in the past few years
indicates that GA–GID1–DELLA is a key regulatory module
that controls plant growth and development by integrating
internal signals from other hormone pathways (auxin, absci-
sic acid, jasmonic acid and ethylene), and external biotic
(pathogen) and abiotic (light conditions, cold and salt
stresses) cues [14,81,82]. Removing DELLA function not
only affects plant growth and development, but also reduces
tolerance to cold and salt stresses, and increases suscepti-
bility to necrotroph pathogens, yet increases resistance to
biotroph pathogens. In many cases, signals from other path-
ways modify GA levels by altering the expression of GA
metabolism genes, which in turn indirectly affect DELLA
stability (Figure 3). Similarly, the GA pathway can affect
levels of other phytohormones by regulating the expression
of genes involved in their metabolism. However, DELLA
also integrates internal and external signals by direct
protein–protein interactions with key regulatory proteins in
these pathways (Figure 3). During de-etiolation, light (medi-
ated by phytochromes) inhibits hypocotyl elongation by
causing degradation of PIFs and also inhibiting GA accumu-
lation and in turn increasing DELLA protein levels (reviewed
in [81]). As described earlier, DELLA inhibits hypocotyl elon-
gation by binding directly to PIFs and preventing expression
of PIF target genes [72,73]. In Arabidopsis fruit, DELLA inter-
acts with another bHLH protein in subfamily-15, ALCATRAZ
(ALC), to inhibit its function in valve margin development [83].
Three additional bHLH subfamily 15 members — PIF1 (PIL5),
SPT and PIL2 — also interact with DELLA in yeast two-hybrid
assays [84], although the biological significance of these
interactions has not been determined.
In addition to playing important roles in affecting light
signaling and fruit patterning pathways, GA inhibits jas-
monic-acid-mediated defense responses [22]. It turns out
that DELLA promotes jasmonic-acid signaling by binding
directly to jasmonic-acid signaling repressors (JAZs), and
this interaction blocks the inhibitory effect of JAZs on the
MYC2 transcription factor (a positive component of jas-
monic-acid signaling) [80]. As described earlier, the
DELLA–SCL3 interaction also integrates GA signaling with
the SCR/SHR-mediated developmental pathway in roots
[75,76]. Taken together, DELLA mediates crosstalk between
the GA pathway and light, jasmonic-acid and developmental
signaling pathways by direct protein–protein interactions
with three distinct types of transcription factor (Figure 3).
Conclusions
The GA–GID1–DELLA signaling module controls plant
growth and development by integrating internal develop-
mental programs and external cues through a complex regu-
latory network. It is fascinating that DELLA interacts with
diverse classes of regulatory protein that function in distinct
pathways. Biochemical and systems biology approaches
will be important for the study of the central role of the DELLA
interactome in modulating plant growth and development.
Comparative studies of the GA–GID1–DELLA signaling
module in early land plants will shed light on the role of
ancient DELLA prior to its recruitment into the GA signaling
pathway.
Acknowledgments
I thank Shinjiro Yamaguchi for help with Figure 1, and Miyako Ueguchi-
Tanaka and Makoto Matsuoka for sharing data before publication. My
research projects are supported by NSF (IOS-0641548 and MCB-
0923723), USDA (2010-65116-20460), and BARD (IS-4018-07).
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