Development 139, 4416-4427 (2012) doi:10.1242/dev.082925
© 2012. Published by The Company of Biologists Ltd
Cell cycle regulates cell type in the Arabidopsis sepal
One fundamental question is how are complex patterns of
specialized cell types self-organized during development? These
patterning processes take place while cells are growing and
proliferating, so coordination of cell type with cell cycle control is
essential, but we are only beginning to understand its mechanism.
The current paradigm is that master regulatory transcription factors
determine the identity of a cell by activating many downstream
genes, including cell cycle regulators such as cyclins and cyclin-
dependent kinases (CDKs). The power of this paradigm is
demonstrated by recent findings that key transcription factors bind
directly to the enhancers of cell cycle genes. For example, the
MYB transcription factor FOUR-LIPS binds to the promoter
directly and represses CDKB1;1 and other cell cycle regulators to
prevent further division of guard cells (Xie et al., 2010). Likewise,
SHORTROOT and SCARECROW bind directly to the
CYCLIND6;1 regulatory region to promote the asymmetric
division of the initial cell daughters to generate cortex and
endodermal layers in the root (Sozzani et al., 2010).
Regulation of the cell cycle is essential for creating the
characteristic pattern of the outer sepal epidermal cells in
Arabidopsis thaliana (Roeder et al., 2010). The sepal is the
outermost green floral organ, which encloses and protects the
developing reproductive organs before the flower blooms (Fig.
1A). The cells in the outer epidermis of Arabidopsis sepals exhibit
a characteristic pattern, with diverse sizes ranging from giant cells
(Fig. 1B) stretching to an average of 360 m in length (about one
fifth the length of the sepal) to the smallest cells reaching only
about 10 m (Roeder et al., 2010). The giant cells have long been
used as a marker for sepal organ identity in the flower (Bowman et
al., 1989; Bowman et al., 1991; Ditta et al., 2004; Pelaz et al.,
2000), but little is known about the development of this cell type.
Giant cells are involved in regulating the curvature of the sepals
(Roeder et al., 2010).
Previously, we have shown that variability in the timing of cell
division is sufficient to produce the wide variety of cell sizes
found within the sepal epidermis (Roeder et al., 2010). Giant
cells form very early in the development of the sepal by stopping
mitotic division and entering endoreduplication, a cell cycle in
which the cell grows and replicates its DNA, but fails to divide
(Breuer et al., 2010; Lee et al., 2009; Traas et al., 1998).
Concurrently, the smaller cells continue to divide, which reduces
their size. The pattern is regulated by CDK inhibitors, which
influence the probability
endoreduplication early and become enlarged. Overexpression of
the CDK inhibitor KRP1 throughout the epidermis causes many
cells to endoreduplicate, resulting in a sepal covered with large
cells (Bemis and Torii, 2007; Roeder et al., 2010). Conversely,
mutations in the SIAMESE family CDK inhibitor loss of giant
cells from organs (lgo) cause an absence of giant cells (Roeder
et al., 2010). A computational model in which the decision to
divide or endoreduplicate is made randomly can reproduce the
cell size distribution within the sepal, suggesting that variability
is important in generating the pattern (Roeder et al., 2011;
Roeder et al., 2010).
Here, we ask whether developmental regulators interact with the
cell cycle to create the characteristic pattern of giant cells and small
cells in the sepal epidermis. We find the expression patterns of two
enhancers distinguish giant cells from small cells, suggesting that
these can be considered to be distinct cell types, as well as cells of
different size and ploidy. Through a forward genetic screen, we
have identified several members of the epidermal specification
pathway, each of which regulates giant cell formation and identity.
We find that giant cell identity is established upstream of
endoreduplication, but that small cell identity appears to be
negatively regulated by endoreduplication directly or indirectly,
indicating that cell cycle regulation can control cell identity, just as
cell identity can control cell cycle.
with which cells enter
1Division of Biology, California Institute of Technology, Pasadena, CA 91125 USA.
2Center for Integrative Study of Cell Regulation, California Institute of Technology,
Pasadena, CA 91125 USA. 3Center for Advanced Computing Research, California
Institute of Technology, Pasadena, CA 91125 USA. 4Sainsbury Laboratory at
Cambridge University, Cambridge CB2 1LR, UK.
*Present address: Weill Institute for Cell and Molecular Biology and Department of
Plant Biology, Cornell University, Ithaca, NY 14853 USA
‡Present address: Developmental Biology Unit, EMBL, Meyerhofstrasse 1, 69117
§Author for correspondence (email@example.com)
Accepted 3 September 2012
The formation of cellular patterns during development requires the coordination of cell division with cell identity specification. This
coordination is essential in patterning the highly elongated giant cells, which are interspersed between small cells, in the outer
epidermis of the Arabidopsis thaliana sepal. Giant cells undergo endocycles, replicating their DNA without dividing, whereas small
cells divide mitotically. We show that distinct enhancers are expressed in giant cells and small cells, indicating that these cell types
have different identities as well as different sizes. We find that members of the epidermal specification pathway, DEFECTIVE KERNEL1
(DEK1), MERISTEM LAYER1 (ATML1), Arabidopsis CRINKLY4 (ACR4) and HOMEODOMAIN GLABROUS11 (HDG11), control the identity
of giant cells. Giant cell identity is established upstream of cell cycle regulation. Conversely, endoreduplication represses small cell
identity. These results show not only that cell type affects cell cycle regulation, but also that changes in the cell cycle can regulate
KEY WORDS: Epidermal specification, Giant cell, Endoreduplication
Adrienne H. K. Roeder1,2,*,§, Alexandre Cunha2,3, Carolyn K. Ohno1,‡and Elliot M. Meyerowitz1,4
Cell cycle regulates cell type
MATERIALS AND METHODS
Enhancer trap markers
One marker from the Poethig collection of enhancer trap lines expressed
in the flowers (ABRC stock number CS70134) showed the small cell
expression pattern. The giant cell marker is enhancer trap line YJ158 from
the Bowman collection (Eshed et al., 2004).
Generation of the fluorescent giant cell marker
The enhancer trap T-DNA driving the giant cell expression pattern is
inserted about 4.7 kb upstream of At5g17700, which encodes a MATE
efflux family protein, and about 1.4 kb downstream of At5g17710, which
encodes a co-chaperone grpE family protein (supplementary material Fig.
S1A). To identify the enhancer element that drives giant cell expression,
we tested a 1 kb fragment immediately upstream of the trap insertion. The
1 kb fragment was PCR
GCTCGAGCCTGTCCGCTATATCATGCAAATC-3?) and oAR214 (5?-
CACCTCGAGATACCTTTTGCGTTCGTTGAACCA-3?), and cloned
into pCRBlunt II TOPO (Invitrogen) to create pAR108. The 1 kb fragment
was cut out of pAR108 with XhoI and cloned into a BJ36 plasmid in both
orientations in front of the 35S minimal –60 promoter and 3X VenusN7 to
create pAR109 (forward) and pAR110 (reverse). The whole reporter
fragments were excised with NotI and cloned into the binary vector
pMLBart to create pAR111 (forward) and pAR112 (reverse)
(supplementary material Fig. S1A). Both constructs were transformed into
Landsberg erecta (Ler) by agrobacterium-mediated floral dipping and
transgenic plants were selected for Basta resistance. In both forward and
reverse orientations, the 1 kb fragment drives strong expression of a
nuclear localized fluorescent protein (3? Venus-N7) in sepal giant cells
(supplementary material Fig. S1B,C). For ease of imaging, we continued
our analysis using the forward 1 kb nuclear localized fluorescent giant cell
We tested whether the entire promoter region of At5g17700 also drives
expression in giant cells. The 4.2 kb promoter region from the start of the
5? UTR up to the YJ158 enhancer trap insertion was PCR amplified with
oAR217 (5?-CCTCGAGGACTTAAACTACAACGCTTGGCT-3?) and
oAR214, and cloned into pENTR D TOPO (Invitrogen) to create pAR118.
The promoter region was recombined into the pBGWFS7 (Karimi et al.,
2002) binary vector upstream of eGFP-GUS to create pAR121. pAR121
was transformed into wild-type Ler plants via agrobacterium-mediated
floral dipping and transgenic plants were selected for Basta resistance. This
At5g17700 promoter drives expression in young giant cells in the sepals;
however, giant cell expression decreases earlier than in either the 1 kb
enhancer or the original giant cell marker (supplementary material Fig.
S1D). This promoter drives additional patterns of expression, including
petal blades, style, gynoecium and large cells in the stem and petioles.
These results suggest that a larger regulatory region modifies the giant cell
Combinations of mutants and markers were made by crossing. Mutants
were genotyped. Plants homozygous for the markers selected by Basta
and/or Kanamycin resistance were imaged.
amplified with oAR215 (5?-
Mutations and genotyping
M2 Ethyl methanesulfonate (EMS) mutagenized Ler seeds were purchased
from Lehle Seeds and examined under a dissecting microscope for the
absence of giant cells in the sepal.
The dek1-4 mutation isolated contains a C to T change at base 6316 of
the CDS, which causes a single amino acid substitution of a cysteine for
conserved arginine 2106 in domain III of the calpain protease
(supplementary material Fig. S2A) (Sorimachi and Suzuki, 2001). The
dek1-4 allele fails to complement the reference dek1-3 (SAIL_384_G07)
allele (data not shown), establishing that the absence of giant cells is due
to the mutation in the DEK1 gene.
The dek1-4 mutation can be PCR genotyped by amplifying with
oAR449 (5?-TGAAGACTGAAAGGACAAAAGGTGC-3?) with a 60°C
annealing temperature followed by digesting the product with BsaAI to
produce a 108 bp wild-type product or a 137 bp mutant product.
The atml1-2 allele isolated in this mutant screen contains a C to T
change at base 1873 of the CDS, which creates a premature stop codon in
place of glutamine 625 truncating C-terminal end of the protein
(supplementary material Fig. S2B). Additional atml1 alleles, atml1-3
(SALK_033408) and atml1-4 (SALK_128172) (Alonso et al., 2003), also
exhibit the absence of giant cells, demonstrating that mutations in atml1
cause this phenotype. The atml1-2 allele, which causes a truncation in the
C-terminal end of the protein after the START domain, acts semi-
dominantly in that heterozygous plants have a variable appearance, ranging
from wild-type numbers of giant cells to a complete loss of giant cells. By
contrast, atml1-3, which is inserted in the homeodomain acts recessively
and has the least severe loss of giant cells phenotype, whereas atml1-4,
which is inserted in the START domain, acts dominantly (heterozygous
plants lack giant cells).
The atml1-2 mutation can be PCR genotyped by amplifying with
oAR316 (5?-AAACAGAGTGGGAACTCAGCG-3?) and oAR299 (5?-
CACTCAGGACAACGTTCATAGCT-3?) followed by digesting the
product with HhaI to produce a 103 bp wild-type product or a 124 bp
The extracellular domain of the receptor kinase ACR4 contains seven
crinkly repeats and three cysteine-rich repeats with homology to the tumor
necrosis factor receptor (TNFR). The acr4-23 allele isolated in this mutant
screen contains a G to A mutation at base 300 of the CDS, which creates
a premature stop codon at amino acid 100 in the extracellular crinkly
repeats (supplementary material Fig. S2C). The acr4-24 allele, which was
also isolated in this mutant screen, contains a G to A change at base 935 of
the CDS, which causes the substitution of a tyrosine for a conserved
cysteine at amino acid 312. This substitution is predicted to disrupt the
formation of a disulfide bond that is involved in the folding of the seventh
crinkly repeat (Gifford et al., 2005). Transformation of acr4-24 with a
wild-type copy of ACR4 rescues both giant cell formation and the fertility
and ovule defects, indicating that all of these phenotypes are caused by
mutations in acr4.
The acr4-23 mutation can be PCR genotyped by amplifying with
oAR304 (5?-GCTATCTCATCAGCCATATTGTTG-3?) and oAR305 (5?-
GTAATCACCAGCACTAACTTCTAA-3?) followed by digesting the
product with BstXI to produce a 90 bp wild-type product or a 109 bp
mutant product. The acr4-24 mutation can be PCR genotyped by
amplifying with oAR302 (5?-ATAGAAGTCCCTGTGAGAACTGCG-3?)
and oAR303 (5?-TATGATCATAGTGCGGTCTGTTGG-3?) followed by
digesting the product with HhaI to produce a 105 bp wild-type product or
a 128 bp mutant product.
The hdg11-3 allele isolated in this screen contains a C to T change at
base 415 of the CDS, which creates a premature stop codon at amino acid
139 of the protein. The reduction in giant cells in hdg11-3 mutants is
strongest immediately following bolting and becomes less pronounced with
age. The reference hdg11-1 (SAIL_865_G09) allele also exhibits a subtle
reduction in giant cells (data not shown). Both alleles exhibit increased
trichome branching as described previously (Nakamura et al., 2006).
Similar to the atml1 alleles, hdg11-3, which truncates the protein in the
zipper loop zipper domain, acts semi-dominantly with heterozygous plants
having a range of phenotypes from wild type to mutant.
The hdg11-3 mutation can be genotyped by PCR amplifying with
oAR300 (5?-GTGAAGATCCTTACTTTGATGAT-3?) and oAR301 (5?-
TCAAGCTATGCAAAAAGATCAAA-3?) and cutting with BclI to
produce a 129 bp wild-type fragment or a 153 bp mutant fragment.
The hdg11-1 allele can be genotyped by PCR amplification with
oAR282 (5?-ATTCTATCACCGGAAGGGAAG-3?), oAR283 (5?-
TGAAGAGAAAGAGACACCCAG-3?) and SLB1 (5?-GCCTTT -
TCAGAAATGGATAAATAGCCT-3?). The wild-type product will be 546
bp and the mutant product 753 bp.
To analyze fluorescent reporters, stage 12 medial adaxial sepals were
removed with a needle, stained with 0.1 mg/ml propidium iodide for 10
minutes and mounted in 0.01% Triton X-100 on a slide under a cover slip.
Sepals were imaged with 10? and 20? objectives on Zeiss 510 Meta or
Zeiss 710 laser scanning confocal microscope. The small cell marker was
4426 RESEARCH ARTICLE
Development 139 (23)
thank Rochelle Diamond and the Caltech Flow Cytometry Facility for expertise
in flow cytometry, Aida Sun for technical assistance with mapping, Will Suh for
technical assistance with cloning, and The Arabidopsis Information Resource
(TAIR) for essential genome information.
This work made use of the Cornell Center for Materials Research Facilities
supported by the National Science Foundation [DMR-0520404]. The authors
acknowledge the Department of Energy Office of Basic Energy Sciences,
Division of Chemical Sciences, Geosciences and Biosciences, Office of Basic
Energy Sciences of the US Department of Energy [DE-FG02-88ER13873 to
E.M.M.] for funding the experimental work described; the Gordon and Betty
Moore Foundation Cell Center (http://www.cellcenter.caltech.edu/) (A.H.K.R.
and A.C.) for funding the computational image analysis and the salary for
A.H.K.R. to finish the project; and a Helen Hay Whitney Foundation
postdoctoral fellowship to A.H.K.R. for her salary in initiating the project.
Competing interests statement
The authors declare no competing financial interests.
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