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Short title: Peptide signaling during vascular differentiation 1
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Peptide signaling pathways in vascular differentiation 3
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Hiroo Fukuda1 & Christian S. Hardtke
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1Department of Biological Sciences, Graduate School of Science, The University of 8
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan 9
2Department of Plant Molecular Biology, University of Lausanne, Biophore Building, 10
CH-1015 Lausanne, Switzerland 11
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One-sentence summary: 13
CLE peptide and related signaling pathways have been assigned prominent roles in the 14
development of both vascular tissues, xylem and phloem. 15
Author contributions: 16
H.F. and C.S.H. wrote the manuscript together. 17
Plant Physiology Preview. Published on December 3, 2019, as DOI:10.1104/pp.19.01259
Copyright 2019 by the American Society of Plant Biologists
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The modern plant vascular system is a central feature of extant angiosperms and 18
consists of xylem, phloem, and the intervening procambium (Lucas et al. 2013). During 19
vegetative growth, the apical meristem serves as a continuous source of procambial 20
initial cells, which produce the primary xylem, the primary phloem, and the 21
procambium. In secondary growth, vascular cambium, which is derived from the 22
procambium, acts as a stem cell reservoir and continues to give rise to secondary xylem 23
and phloem cells. The formation of the vascular tissue is a well-organized plant 24
developmental process, whose central step is the regulation of vascular stem cell fates. 25
It is governed by cell-to-cell communication, and symplastic movement of signaling 26
molecules contributes to vascular development. Various secreted peptides as well as 27
plant hormones play crucial roles in cell-to-cell communication for regulating vascular 28
development (Fukuda and Ohashi-Ito, 2019). Among the peptides, several members of 29
the CLAVATA3 (CLV3)/EMBRYO SURROUNDING REGION (ESR) (CLE) family 30
act at different points of key processes in vascular development (Fukuda and 31
Ohashi-Ito, 2019; Hazak and Hardtke, 2016). The CLE family genes are conserved 32
among land plants. In the Arabidopsis (Arabidopsis thaliana) genome, there are 32 33
genes encoding 27 distinct CLE peptides (Yamaguchi et al. 2016). CLE precursor 34
proteins contain an N-terminal signal peptide and at least one conserved C-terminal 35
12-14 amino-acid CLE domain, from which a mature CLE peptide is produced through 36
proteolytic cleavage. The activity of some processed peptides is increased by 37
modifications such as hydroxylation on proline residues, and in some cases by 38
glycosylation with three arabinose residues (Ito et al. 2006; Ohyama et al. 2009; 39
Matsubayashi, 2011; Shinohara and Matsubayahi, 2013). During vascular development, 40
CLE41/CLE44, CLE45, and CLE9/CLE10 peptides function in distinct processes. In 41
addition, other peptides such as phytosulfokine and EPIDERMAL PATTERNING 42
FACTOR-LIKE (EPFL) peptides are thought to contribute to the regulation of vascular 43
development (Holzwart et al. 2018; Ikematsu et al. 2017). Crosstalk among peptides and 44
between peptides and plant hormones is an important current topic in vascular 45
development. In this update, we focus on recent advances in our understanding of the 46
regulation of vascular fate with an emphasis on peptide signaling. 47
The TDIF-TDR/PXY signaling pathway in xylem differentiation 48
TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF) is a 49
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CLE-family peptide composed of twelve amino acids including two hydroxylated 50
proline residues (Ito et al. 2006). TDIF was first isolated from zinnia (Zinnia elegans) 51
xylogenic culture medium as a factor inhibiting tracheary element differentiation (Ito et 52
al. 2006). The TDIF sequence is conserved in the genome of Euphyllophytes (Hirakawa 53
and Bowman, 2015) and encoded by the CLE41 and CLE44 genes in the Arabidopsis 54
genome (Hirakawa et al. 2008). The activity of TDIF in vascular development is also 55
conserved among extant Euphyllophytes (Hirakawa and Bowman, 2015). TDIF 56
RECEPTOR/PHLOEM INTERCALATED WITH XYLEM (TDR/PXY) was 57
demonstrated to be a TDIF receptor (Hirakawa et al. 2008). TDR/PXY belongs to Class 58
XI LEUCINE-RICH REPEAT RECEPTOR-LIKE KINASES (LRR-RLK), which 59
consist of an extracellular LRR domain, a single transmembrane domain for anchorage 60
in the plasma membrane, and a cytoplasmic kinase domain (Fisher and Turner, 2007; 61
Hirakawa et al. 2008). The extracellular domain of TDR forms a twisted right-handed 62
superhelical structure, comprising 22 LRRs and the N-terminus, and specifically 63
recognizes TDIF by its inner concave surface (Morita et al., 2016, Zhang et al., 2016a). 64
The crystal structure of TDR ectodomains contains N-linked glycans (Zhang et al., 65
2016b). The PXY (TDR) family (PXYf) is comprised of TDR (PXY), PXY-LIKE1 66
(PXL1), and PXY-LIKE2 (PXL2) (Fig. 1A). PXL1 and PXL2 also participate in vascular 67
development together with TDR, since TDIF binds the ligand binding pocket of both 68
PXL1 and PXL2 (Zhang et al., 2016b), and pxl1 and pxl2 mutations enhance the 69
vascular organization defects in tdr mutants (Etchells et al., 2013; Fisher and Turner, 70
2007). SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) family proteins 71
(SERK1 and others) act as co-receptors of TDR (Fig. 1A; Zhang et al., 2016b). In the 72
TDIF-TDR-SERK2 complex, TDIF mediates interactions between the LRRs of TDR 73
and SERK2. Similarly, the CLE42 peptide, the closest homolog of TDIF that also 74
displays TDIF activity (Ito et al., 2006), promotes an interaction between PXL2 and 75
SERK2 (Mou et al., 2017). Because SERK2 does not change the basic structure of the 76
TDIF-TDR complex, TDIF functions as a “glue” that joins TDR and a SERK, which 77
may contribute to phosphorylation of a cytoplasmic downstream factor (Zhang et al., 78
2016b). 79
In plants, the TDIF-TDR signaling module acts by inhibiting xylem 80
differentiation from procambial cells and promoting procambial cell proliferation, 81
which results in the maintenance of the procambial cell population (Hirakawa et al. 82
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2008). WOX4, which is a member of the WUSCHEL-RELATED HOMEOBOX (WOX) 83
gene family, is a downstream factor of TDR and promotes procambial cell divisions 84
(Fig. 1A; Ji et al. 2010; Hirakawa et al. 2010; Suer et al. 2011). Moreover, the SK1 85
[ARABIDOPSIS THALIANA SK11 (ATSK11), ATSK12, and ATSK13] and SK2 86
[BRASSINOSTEROID-INSENSITIVE2 (BIN2), BIN2-LIKE1 (BIL1), and BIL2] 87
subgroups of GLYCOGEN SYNTHASE KINASE3/SHAGGY-LIKE KINASE proteins 88
(GSK3s) contribute redundantly to suppress xylem differentiation downstream of TDR 89
(Fig. 1A). 90
Promotion of procambial/cambial cell proliferation by TDIF-TDR 91
TDR is expressed preferentially in procambium and cambium (Hirakawa et al. 2008; 92
Fisher and Turner 2007), while CLE41 and CLE44 are expressed specifically in phloem 93
and more widely in its neighboring cell files, respectively (Fig. 1A; Hirakawa et al. 94
2008). Defects in TDR or CLE41 cause the depletion of the procambial cells (Fisher and 95
Turner 2007, Hirakawa et al. 2008, 2010, Etchells and Turner 2010). Ectopic expression 96
of CLE41 under different promoters revealed that expression of CLE41 in or around 97
procambial cells is sufficient to drive vascular cell division, but localized expression of 98
CLE41 in the phloem is required for maintaining properly orientated cell divisions 99
(Etchells and Turner 2010). Thus, phloem-synthesized TDIF regulates the orientation of 100
procambial cell divisions in a non-cell-autonomous fashion. 101
TDIF upregulates WOX4 expression in a TDR-dependent manner (Hirakawa 102
et al. 2010). Genetic analyses showed that WOX4 is required to promote the 103
proliferation of procambial/cambial cells, but not for repressing xylem differentiation in 104
response to the TDIF signal. The WOX14 transcription factor may also function 105
redundantly in Arabidopsis to modulate procambial cell proliferations (Etchells et al., 106
2013). Moreover, WOX14 may act in xylem fiber differentiation through promotion of 107
gibberellin biosynthesis (Denis et al., 2017), consistent with the requirement of 108
gibberellin for xylem expansion (Ragni et al., 2011) (Fig. 1A). Although WOX4 was 109
shown to interact physically with the HAIRY MERISTEM (HAM) family protein 110
HAM4 (Zhou et al., 2015), it is still unknown how WOX4 regulates gene expression 111
with HAM proteins. 112
The cambium plays a central role in radial growth of woody plants. In the 113
poplar (Populus trichocarpa) genome, orthologs of CLE41, TDR/PXY, and WOX4 are 114
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conserved (Hirakawa and Bowman, 2015, Etchells et al., 2015, Kucukoglu et al., 2017), 115
and PttWOX4a and PttWOX4b are specifically expressed in the cambial region during 116
vegetative growth, but not after growth cessation and during dormancy (Kucukoglu et 117
al., 2017). A decrease in PttWOX4a/b levels achieved by RNAi treatment caused severe 118
reduction of the width of the vascular cambium and greatly diminished secondary 119
growth, although primary growth was not affected. 120
Because there is no homologous sequence to Arabidopsis WOX14 in poplar 121
or spruce (Picea) genomes, WOX4 is expected to be a major player of cambial 122
proliferation in woody plants. PtPP2::PttCLE41-PttANT::PttPXY double 123
overexpression lines, in which phloem-specific expression of PttCLE41 and 124
cambium-specific expression of PXY are induced, exhibited highly organized vascular 125
tissue, comparable to that of wild-type controls (Etchells et al., 2015). Because 126
orthologs of CLE41, TDR/PXY, and WOX4 are widely distributed in angiosperm and 127
gymnosperm tree species (Hirakawa and Bowman, 2015, Kucukoglu et al., 2017), the 128
TDIF-TDR/PXY-WOX4 pathway is an evolutionarily conserved program for the 129
regulation of the vascular cambium activity in wood formation. Recently two groups 130
identified bifacial, strongly proliferating cambial stem cells that feed both xylem and 131
phloem production during secondary growth in Arabidopsis (Shi et al., 2019, Smetana 132
et al. 2019). In fact, in the cambial stem cells, TDR/PXY and WOX4 genes were actively 133
expressed. Recently, Zhu and others found that PtrCLE20 is expressed in xylem cells 134
and represses cambium activity in poplar (Zhu et al. 2019). The molecular mechanism 135
underlying the xylem-producing CLE peptide-dependent regulation of cambium activity 136
should be analyzed further. 137
Interaction of the TDIF-TDR pathway with phytohormones 138
The role of auxin in the regulation of vascular cambium activity is well established and 139
the auxin concentration gradient peaks over the cambial region and decreases towards 140
the surrounding secondary tissues in hybrid aspen (Populus tremula L. x Populus 141
tremuloides Michx) (Tuominen et al., 1997). WOX4 has been shown to be necessary 142
both for the auxin responsiveness of the cambium cells and for the auxin-dependent 143
increase in the cambium cell division activity (Suer et al., 2011). Local auxin signaling 144
in TDR-positive stem cells stimulates cambium activity (Brackmann et al. 2018). An 145
analysis with a highly sensitive auxin response marker revealed a moderate auxin 146
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response in TDR-positive stem cells and a higher response in xylem and phloem tissues. 147
Whereas the auxin response factors (ARFs) ARF3 and ARF4 act redundantly as general 148
cambium activators, MONOPTEROS (MP)/ARF5 acts as an inactivator specifically in 149
cambium stem cells (Fig. 1A). Indeed, MP induction resulted in both WOX4 repression 150
and the induction of xylem- and phloem-related genes (Brackmann et al. 2018). 151
Recently, Smetana and others proposed that auxin-dependent WOX4 regulation occurs 152
in xylem precursor cells with an auxin maximum, which promotes division of vascular 153
stem cells in a non-cell autonomous manner (Smetana et al., 2019). This idea should be 154
verified from various viewpoints. 155
Periclinal and radial cell divisions in procambial cells of the root apical 156
meristem (RAM) are also regulated by two bHLH transcription factors, LONESOME 157
HIGHWAY (LHW) and TARGET OF MONOPTEROS 5 (TMO5) (Schlereth et al., 158
2010). In xylem precursor cells in the RAM, auxin induces TMO5 expression, which 159
allows the formation of heterodimers between LHW and TMO5 (Fig. 1B). The 160
heterodimers directly promote the expression of target genes involved in the final step 161
of cytokinin biosynthesis, LONELY GUY 3 (LOG3) and LOG4 (Ohashi-Ito et al., 2014, 162
De Rybel et al., 2014). Therefore, cytokinin was hypothesized to act as a mobile signal 163
from the xylem to trigger divisions in the neighboring procambium cells. DOF2.1 and 164
its closest homologs, TMO6 and DOF6, may be key transcription factors downstream of 165
cytokinin in terms of procambial cell proliferation (Smet et al., 2019, Miyashita et al., 166
2019). In xylem precursor cells, however, LHW-TMO5-induced HISTIDINE 167
PHOSPHOTRANSFER PROTEIN 6 (AHP6) represses cytokinin signaling to inhibit 168
cell proliferation (Ohashi-Ito et al., 2014, De Rybel et al., 2014). 169
Suppression of xylem differentiation from procambial cells 170
TDIF signaling releases BIN2 and BIL2, but not BIL1, from TDR, and then activates 171
these GSK3s, which results in the suppression of xylem differentiation (Fig. 1A; Kondo 172
et al., 2014). Conversely, the inhibition of GSK3s with a chemical inhibitor (De Rybel 173
et al., 2009), bikinin, induces xylem differentiation (Kondo et al., 2014, 2015). 174
Bikinin-dependent ectopic xylem differentiation is suppressed in loss-of-function 175
mutants for BRI1-EMS-SUPPRESSOR 1 (BES1) (Kondo et al., 2016, Saito et al., 2018), 176
a direct substrate of GSK3s in the brassinosteroid signaling pathway (Yin et al., 2002). 177
By contrast, constitutively active BES1 (bes1-D) promotes xylem differentiation 178
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(Kondo et al., 2014). The loss-of-function mutant of BRASSINAZOLE RESISTANT 1 179
(BZR1), the closest homolog of BES1, also shows a bes1-like phenotype, but a weaker 180
one (Saito et al., 2018). Thus, BES1 and BZR1, which are suppressed by GSK3s, act 181
redundantly in promoting xylem differentiation (Fig. 1A). Further analysis indicated 182
that the GSK3s-BES1/BZR1 signal not only regulates xylem but also phloem 183
differentiation (Kondo et al., 2016, Saito et al., 2018). This finding is consistent with a 184
previous report showing that both bes1-D and bzr1-D partially rescued the phenotype of 185
the octopus mutant, in which root protophloem differentiation is suppressed (Anne et al., 186
2015), and with a role of brassinosteroid signaling in phloem sieve element 187
differentiation (Kang et al., 2017). Nevertheless, whether the canonical brassinosteroid 188
pathway effectors also have a role in root protophloem development remains unclear 189
(Kang et al., 2017). Of SK1 and SK2 GSK3s, BIL1 may have a distinct role in vascular 190
development (Fig. 1A). Han and others suggested that BIL1 phosphorylates and 191
activates MP, and the activated MP promotes the expression of two A-type Arabidopsis 192
Response Regulators (ARRs), ARR7 and ARR15, which suppress cambial cell 193
divisions (Han et al., 2018). 194
The finding that bikinin induces ectopic xylem cell differentiation led to the 195
establishment of a useful tissue culture system for vascular cell differentiation named 196
VISUAL (Vascular cell Induction culture System Using Arabidopsis Leaves). In 197
VISUAL, mesophyll cells in cultured cotyledons or leaf disks differentiate at a high 198
frequency into tracheary elements and sieve elements via the procambial stage in the 199
presence of bikinin (Kondo et al., 2015, 2016). This system enabled the analysis of the 200
roles of various genes in vascular differentiation by using their mutants as starting 201
materials of VISUAL. 202
Brassinosteroid signaling may interact with the 203
TDIF-TDR-GSK3s-BES1/BZR1 signaling pathway, because GSK3s and BES1/BZR1 204
are among its key components (Fig. 1A). Indeed, brassinosteroid promotes xylem 205
differentiation (Yamamoto et al, 1997, Caño-Delgado et al., 2004, Kubo et al, 2005), 206
which suggests that brassinosteroid regulates procambial cell fates to counteract TDIF 207
signaling through the reverse regulation of GSK3s. BRASSINOSTEROID 208
INSENSITIVE 1 (BRI1) is the major receptor for brassinosteroid and the BRI1 gene is 209
expressed widely in plants, while its homologs, BRI1-LIKE 1 (BRL1) and 3 (BRL3), are 210
expressed predominantly in vascular tissues. In particular, BRL1 expression is 211
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associated with the procambial cells in inflorescence stems (Caño-Delgado et al., 2004). 212
In procambial cells, therefore, the TDIF and brassinosteroid signals may be balanced 213
via GSK3s to determine procambial cell identity. Because brassinosteroid biosynthesis 214
occurs in procambial cells, which is promoted by auxin and cytokinin (Yamamoto et al., 215
2001, 2007), brassinosteroid may act as an autocrine factor in xylem differentiation 216
from procambial cells. 217
CLE9/CLE10 perception in xylem formation 218
CLE9 and CLE10, which encode the same CLE peptide, are preferentially expressed in 219
vascular cells of roots (Fig. 1B; Kondo et al. 2011). cle9 mutants and cle9 cle10 double 220
mutants exhibit a phenotype of increased metaxylem cell file numbers, which results 221
from enhanced periclinal cell division of xylem precursor cells in the RAM (Qian et al., 222
2018). The receptor kinase HAESA-LIKE1 (HSL1) is a CLE9/10 receptor that regulates 223
stomatal lineage cell division, while BARELY ANY MERISTEM (BAM) class 224
receptor kinases are CLE9/10 receptors that regulate periclinal cell division of xylem 225
precursor cells (Fig. 1B; Qian et al., 2018). Both HSL1 and BAM1 bind to CLE9/10, 226
but only HSL1 recruits SERKs as co-receptors in the presence of CLE9/10, suggesting 227
different signaling modes for these receptor systems (Hazak et al., 2017; Qian et al., 228
2018). Genetic analysis indicated that BAM1, BAM2, and BAM3 are involved in the 229
action of CLE9/10, but BAM1 is most important among them. Their genes are 230
expressed in vascular cells, with BAM1 being expressed in xylem and phloem precursor 231
cells in roots, consistent with the function of CLE9/10 in xylem precursor cells. 232
Application of CLE9/10 peptide suppressed protoxylem vessel formation in 233
Arabidopsis roots (Kondo et al., 2011). An early event caused by exogenous CLE9/10 234
peptide was the reduced expression of type-A ARR genes such as ARR5 and ARR6, 235
which are negative regulators of cytokinin signaling (Fig. 1B). Consistently, an arr10 236
arr12 double mutant, which is a combination of mutations of B-type ARRs, showed 237
CLE9/10-resistance in terms of protoxylem vessel suppression, and displayed ectopic 238
protoxylem vessel formation (Kondo et al., 2011). Therefore, CLE9/10 signaling may 239
control xylem differentiation through a cytokinin signaling pathway. However, because 240
cle9 cle10 double mutants did not enhance protoxylem vessel differentiation, other CLE 241
peptide(s) may also be involved redundantly in this process. 242
Phytosulfokine peptide perception in procambial cell fate 243
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Phytosulfokines (PSKs) are sulfated pentapeptides that are perceived by 244
PHYTOSULFOKINE RECEPTOR-1 and -2 (PSKR1/PSKR2) (Matsubayashi et al., 245
2002). PSK stabilizes the PSKR island domain for recruitment of a SERK (Wang et al., 246
2015). A recent study revealed a small RECEPTOR-LIKE PROTEIN 44 247
(RLP44)-mediated interaction between PSKRs and BRI1 that regulates procambial cell 248
fate in roots (Fig. 1B; Holzwart et al. 2018). In the rlp44 loss-of-function mutant, 249
supernumerary metaxylem-like cells are formed frequently outside the primary xylem 250
axis in the position of the procambium. This rlp44 phenotype can be rescued by 251
application of PSK peptide. Moreover, pskr1 pskr2 double mutants displayed an 252
rlp44-like xylem phenotype. Likewise, bri1 mutants show ectopic xylem in the 253
procambial position, while brassinosteroid-deficient mutants do not exhibit an 254
rlp44-like xylem phenotype. Therefore, PSK-PSKR signaling acts to maintain 255
procambial cell identity and RLP44 mediates the interaction between PSKR1 and BRI1. 256
These results may provide a model for the integration of multiple signaling pathways at 257
the plasma membrane by shifting associations of receptors in multiprotein complexes in 258
response to different ligands (Holzwart et al. 2018). Because RLP44 and most PSK 259
genes are expressed preferentially in xylem/phloem and procambium of roots, 260
respectively, this signaling may occur in a non-cell autonomous fashion. 261
ERECTA and related receptors cooperate with TDR/PXY family receptors 262
The LRR-RLK encoded by the ERECTA (ER) gene is part of a small gene family 263
together with ER-LIKE1 (ERL1) and ERL2. In er erl1 stems, intervening cambial cells 264
are decreased and phloem cells are frequently located adjacent to xylem cells (Uchida 265
and Tasaka, 2013). This also occurs in tdr (Fisher and Turner, 2007; Hirakawa et al., 266
2008), suggesting that ER and ERL1, like TDR, act by suppressing xylem 267
differentiation and promoting cambial cell activity. By contrast, er erl1 hypocotyls 268
display a remarkable expansion of the xylem and an increase in xylem fiber cells (Ragni 269
et al., 2011; Ikematsu et al., 2017). 270
On the one hand, this result supports the idea that ER and ERL1 suppress 271
xylem differentiation but appear to suppress cambial activity. On the other hand, the 272
relative xylem expansion in the Landsberg er (Ler) genotype was found to be due to 273
early cessation of phloem formation and reduced cambial activity (Sankar et al., 2014). 274
The difference between stems and hypocotyls in er erl1 may be explained by the 275
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tissue-specific gene regulation of ERL1 and ERL2: In the er pxy pxl1 pxyl2 genetic 276
background, ERL1 and ERL2 gene expression is reduced greatly in stems, while their 277
expression is strikingly enhanced in hypocotyls (Wang, et al., 2019). These findings 278
clearly indicate a tight interaction between PXY family genes and ER family genes (Fig. 279
1A). Indeed, the sextuple mutant, er erl1 erl2 pxy pxl1 pxyl2 shows a complete 280
suppression of secondary growth of hypocotyls, supporting the view that both TDR and 281
ER family genes are crucial factors of secondary growth (Wang, et al., 2019). 282
Both ER and ERL1 are expressed widely in the epidermis, phloem, and xylem 283
(Uchida and Tasaka, 2013), but the vascular defect in er erl1 stems is rescued by 284
phloem-specific activity of ER (Uchida and Tasaka, 2013), consistent with a proposed 285
role of ER in phloem proliferation (Sankar et al., 2014). Therefore, ER ERL1-dependent 286
suppression of xylem precursor cell division should occur in a non-cell autonomous 287
manner (Fig. 1A; Tamashige et al., 2017). ER and ERL1 also function in preventing 288
xylem fiber differentiation, which is mediated by the NAC SECONDARY WALL 289
THICKENING PROMOTING FACTORs (NSTs) in hypocotyls (Ikematsu et al., 2017). 290
Although BREVIPEDICELLUS is required for the hypocotyl to gain competency to 291
respond to gibberellin and trigger fiber differentiation in both the wild-type and er erl1, 292
it is still unknown whether the ER/ERL1 pathway is associated with the gibberellin 293
pathway. 294
Ligands for ER and EFR1 that function in xylem development have not been 295
identified. However, it is known that EPIDERMAL PATTERNING FACTOR 1 (EPF1), 296
EPF2, and EPF-LIKE9 (EPFL9) peptides function as ligands for ER and ERL1 in 297
stomata development (Han and Torii, 2016). In stem elongation, EPFL4 and EPFL6, 298
which are produced in epidermal cells, act as ligands for phloem-located ER (Abrash et 299
al., 2011; Uchida et al., 2012). In hypocotyls, EPFL4 and EPFL6 are expressed in 300
xylem parenchyma cells and differentiating xylem cells (Wang, et al., 2019). However, 301
there is presently no evidence that EPFL4 and EPFL6 function as ligands for regulating 302
hypocotyl secondary growth. In the Arabidopsis genome, there are 11 EPF/EPFL family 303
members (Hara et al., 2009). It is plausible that some EPF/EPFL family members may 304
function as ligands for ER and ERL1 to suppress xylem development in stems and 305
hypocotyls. TOO MANY MOUTHS (TMM) and SERK family proteins function as 306
co-receptors in ER signaling (Hang and Torii, 2016). Therefore, a specific combination 307
of ER/ERL1, EPF/EPFL peptides, and co-receptors, such as TMM and SERK family 308
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proteins, may function in vascular development in stems and hypocotyls. 309
Phloem-related CLE peptide signals 310
An interesting aspect emerging from the analysis of pxy/tdr and related mutants is that 311
they do not lose their capacity to produce proper xylem and phloem tissues, as judged 312
from morphological and molecular-genetic criteria (Fisher and Turner, 2007; Hirakawa 313
et al., 2008). This even holds true for higher order (sextuple) mutants that largely 314
remove redundancy (Wang et al., 2019). Thus, the main role of the 315
PXY/TDR-CLE41/44/TDIF system is likely the organization of vascular patterning, 316
which is, for instance, evident in the regular spacing of phloem strands during hypocotyl 317
expansion (Sankar et al., 2014). 318
An easier, more accessible system to study a possibly autonomous role of 319
CLE peptide signaling in vascular development is the root tip with its simple diarch 320
vascular organization. Here, two protophloem poles flank a central xylem axis and 321
allow continuous observation of development along a spatio-temporal gradient. 322
Moreover, protophloem expresses key players or markers, such as ALTERED PHLOEM 323
DEVELOPMENT (APL) (Bonke et al., 2003) or COTYLEDON VASCULAR PATTERN 2 324
(CVP2) (Carland and Nelson, 2004; Rodriguez-Villalon et al., 2015), that are also 325
expressed in secondary phloem development (Lehmann and Hardtke, 2016), indicating 326
that the principal findings in one context likely apply to the other. 327
Root-active CLE peptides are perceived in the phloem 328
The root protophloem is also a system where a key question can be answered: Is CLE 329
peptide signaling required to form functional phloem? Early hints that CLE peptides 330
could play a role in root development came from the observation that several CLE genes 331
are expressed in the root (Jun et al., 2010), and that treatments with many chemically 332
synthesized CLE peptides suppress root growth (Fiers et al., 2005; Ito et al., 2006; 333
Kinoshita et al., 2007). Such so-called “root-active” CLE peptides were also employed 334
to identify components that are necessary for CLE peptide perception in the root, and 335
notably identified the receptor-like protein CLV2 and its interacting partner, the 336
pseudokinase SUPPRESSOR OF OVEREXPRESSION OF LLP1-2/CORYNE 337
(SOL2/CRN) (Jeong et al., 1999; Miwa et al., 2008; Muller et al., 2008; Meng and 338
Feldman, 2010). 339
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Both clv2 and crn mutants display substantial resistance to root growth 340
inhibition by a range of root-active CLE peptides, and both the CLV2 and CRN genes 341
are essentially expressed at low levels throughout the root (Hazak et al., 2017). 342
However, recently it was shown that restricted expression of CRN in the developing 343
protophloem is sufficient to fully recover CLE perception in a crn null mutant 344
background (Hazak et al., 2017). This matched the observation that root-active CLE 345
peptides a priori suppress protophloem sieve element differentiation 346
(Rodriguez-Villalon et al., 2014; Hazak et al., 2017), which is essential for root growth 347
(Furuta et al., 2014; Rodriguez-Villalon et al., 2014). Given that interactions between 348
CLE peptides and their cognate receptors are rather specific (Hohmann et al., 2017), the 349
requirement of the CLV2|CRN heteromer for perception of root-active CLE peptides 350
likely reflects a more general rate-limiting role in receptor complex activity. For 351
example, it has been suggested that CLV2|CRN stabilizes the expression of BAM3, the 352
cognate CLE45 receptor in the root (Kang and Hardtke, 2016; Hazak et al., 2017). 353
Suppression of CLE peptide signaling permits root protophloem sieve element 354
differentiation 355
CLE45 is one of the few CLE peptides that is expressed in the developing protophloem 356
sieve elements, the others being the related CLE25 and CLE26 peptides 357
(Rodriguez-Villalon et al., 2014; Anne et al., 2018; Ren et al., 2019). Recently, it was 358
suggested that CLE25 is required for protophloem sieve element formation, although a 359
cle25 mutant did not display a root growth phenotype and only showed a marginal delay 360
in sieve element elongation (Ren et al., 2019). While this might reflect redundancy with 361
other CLE peptides, expression of a supposedly dominant negative mutant version of 362
CLE25 (a G6T exchange in the peptide) abolished protophloem sieve element 363
differentiation as well as one of the formative divisions in the phloem lineage (Ren et al., 364
2019). 365
Interestingly, such divisions can also be suppressed by mild auxin antagonist 366
treatment (Rodriguez-Villalon et al., 2014) and appear to be non-essential. However, it 367
often remains unclear which of the two successive periclinal formative divisions in the 368
phloem lineage is affected, and it might very well turn out that one of them is essential 369
for sieve element formation. Nonetheless, the CLE25G6T
phenotype strongly resembles 370
the so-called Disturbed Protophloem Syndrome observed in backgrounds with elevated 371
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13
CLE45 signaling (Rodriguez-Villalon et al., 2014; Anne and Hardtke, 2017) and is 372
consistent with simple dominant (rather than dominant negative) action of the 373
CLE25G6T
version, as observed for other CLE peptides in other contexts (Czyzewicz et 374
al., 2015), including CLE45G6T
in protophloem formation (Rodriguez-Villalon et al., 375
2014; Czyzewicz et al., 2015). This interpretation is also consistent with observations in 376
pertinent receptor mutants. For example, neither crn loss-of-function mutants, nor 377
CLE-RESISTANT RECEPTOR KINASE (clerk) loss-of-function mutants, which are both 378
strongly resistant to CLE25, CLE26, and CLE45 application, display any root growth or 379
protophloem sieve element differentiation phenotypes (Hazak et al., 2017; Anne et al., 380
2018). The same applies to the crn clerk double mutant (Anne et al., 2018). 381
In summary, current data suggest that CLE peptide signaling is not required 382
per se for sieve element formation in the Arabidopsis root. On the contrary, it seems that 383
suppression of autocrine CLE peptide signaling is a pre-requisite for proper 384
protophloem sieve element differentiation (Breda et al., 2019). This does not, however, 385
preclude a role in other aspects of root development, for example formative divisions or 386
radial organization. For instance, CLE9 and CLE10 redundantly appear to affect 387
formative xylem divisions in the root, through their interaction with the BAM1 and 388
BAM2 receptors (Qian et al., 2018). Such mechanisms may also exist for phloem 389
formation. 390
CLE peptide signaling as rapid mediators of stress-induced sink shutdown 391
Beyond purely developmental aspects, CLE peptides may also transmit environmental 392
inputs, and these two roles might not be mutually exclusive in the case of individual 393
peptides. Indeed, CLE25 is a prime example in this context. In addition to its expression 394
in the protophloem, CLE25 expression is induced by drought stress and acts as a 395
long-distance signal that is transported through the vasculature to convey this 396
physiological state to the shoot system (Takahashi et al., 2018). Coincidentally, such 397
induction should also suppress protophloem differentiation and thereby root growth 398
(Anne and Hardtke, 2017; Hazak et al., 2017), which could be advantageous in drought 399
conditions. Yet another example is the root-active CLE peptide, CLE14, which is 400
induced upon phosphate starvation and triggers a breakdown of root meristem 401
maintenance and root growth (Gutierrez-Alanis et al., 2017). Since this response 402
requires the CLV2|CRN module, it appears that it is achieved through a shutdown of 403
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14
protophloem formation (Meng and Feldman, 2010; Gutierrez-Alanis et al., 2017; Hazak 404
et al., 2017). 405
In summary, beyond any positive developmental roles in phloem development 406
that largely remain to be discovered, root-active CLE peptides might be mainly 407
involved in the sensing of adverse environmental conditions. From the current data, it 408
seems that their upregulation in response to such adverse conditions suppresses 409
protophloem differentiation and thereby halts root growth. From a physiological 410
perspective, such a mechanism would be a very efficient and rapid way to stop growth 411
and eliminate a metabolic sink that finds itself in sub-optimal conditions. Because 412
phloem transport is essentially auto-regulated, this would “automatically” redirect 413
phloem sap to actively growing roots. Thus, CLE peptide regulation may primarily 414
serve to fine-tune and optimize root system exploration of the wildly heterogenous soil 415
matrix, which could represent a substantial adaptive advantage. 416
Concluding remarks 417
In summary, peptide signaling pathways have been increasingly implicated in vascular 418
development over recent years (Figure 1 summarizes peptide and hormone signaling 419
pathways discussed in this update). From the current data, it appears clear that various 420
peptides and plant hormones not only function as ligands in vascular cell proliferation, 421
but also in both xylem and phloem cell type fate regulation, and both in a 422
cell-autonomous or non-cell autonomous manner. In addition, the emerging picture is 423
becoming considerably complex since the exact impact of a given signaling pathway 424
seems to depend on the developmental stage or the organ. For example, the TDIF-TDR 425
signaling pathway apparently acts in the cambium and actively proliferating 426
procambium of hypocotyls and stems, but not in the root apical meristem. Moreover, 427
the picture is complicated by the observation that at least in the RAM context, 428
CLE45-BAM3 signaling has to be suppressed to permit phloem differentiation, 429
although CLE peptide signaling might be required to initiate proper phloem formation. 430
From the genetic analyses, it is also apparent that the complex network composed of 431
multi-signaling pathways makes the regulation of procambial/cambial cell identity and 432
proliferation robust. Similar redundancy might exist at the level of differentiation of 433
vascular tissues, and future efforts could focus on uncovering such redundancy through 434
genetic as well as biochemical/cell biological investigations. 435
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15
436
FIGURE LEGENDS 437
Figure 1. Peptide-related signaling pathways that regulate proliferation of 438
procambial/cambial cells and their differentiation into xylem and phloem cells. A: 439
Signaling pathways in hypocotyls and stems. B: Signaling pathways in the root apical 440
meristem. BR: brassinosteroid; CK: cytokinin; AHKs: cytokinin receptors. 441
442
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16
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696
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ADVANCES
• Various peptides and plant hormones function as ligands in vascular cell proliferation, as well as in xylem and phloem cell type fate regulation, in both a cell-autonomous or non-cell autonomous manner.
• The role of a given signaling pathway can be context-dependent and depend on the developmental stage or the organ.
• The complex network composed of multiple intersecting signaling pathways renders the regulation of procambial/cambial cell identity and proliferation robust.
• CLE peptide signals might convey environmental inputs as a rapid control of sink organ development.
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OUTSTANDING QUESTIONS
• How does crosstalk between different peptide signaling pathways occur mechanistically during vascular development? Do different receptors form a complex on the plasma membrane, and/or are there signaling hubs that connect different signaling pathways?
• Are long-distance peptide signaling pathways controlling vascular development?
• Are the peptide processing and secretion processes regulated as a function of vascular development?
• What are the mechanisms that underlie developmental stage- and organ-specific peptide signaling?
• Where do the processed peptides act at high spatio-temporal resolution?
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