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Running Title: Control of panicle traits by OsGRF4 1 2 3 OsGRF4 controls grain shape, panicle length and seed 4 shattering in rice 5 6 Pingyong Sun 1, 2, 3† , Wuhan Zhang 2, 3† , Yihua Wang 4 , Qiang He 2, 3 , Fu Shu 2, 3 , Hai Liu 2 , Jie Wang 2 , 7 Jianmin Wang 2 , Longping Yuan 2, 3 , Huafeng Deng 2, 3 * 8 1 College of Agronomy, Hunan Agricultural University, Changsha 410128, China, 2 State Key 9 Laboratory of Hybrid Rice, Hunan Hybrid Rice Research Center, Hunan Academy of Agricultural 10 Sciences, Changsha 410125, China, 3 Collaborative Innovation Center of Grain and Oil Crops in 11 South China, Changsha 410128, China, 4 State Key Laboratory for Crop Genetics and Germplasm 12 Enhancement, Nanjing Agricultural University, Nanjing 210095, China. These authors 13 contributed equally to this work. 14 * Correspondence: [email protected]. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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Running Title: Control of panicle traits by OsGRF4 1 

OsGRF4 controls grain shape, panicle length and seed 4 

shattering in rice 5 

Pingyong Sun1, 2, 3†, Wuhan Zhang2, 3†, Yihua Wang4, Qiang He2, 3, Fu Shu2, 3, Hai Liu2, Jie Wang2, 7 

Jianmin Wang2, Longping Yuan2, 3, Huafeng Deng2, 3* 8 

1 College of Agronomy, Hunan Agricultural University, Changsha 410128, China, 2 State Key 9 

Laboratory of Hybrid Rice, Hunan Hybrid Rice Research Center, Hunan Academy of Agricultural 10 

Sciences, Changsha 410125, China, 3 Collaborative Innovation Center of Grain and Oil Crops in 11 

South China, Changsha 410128, China, 4 State Key Laboratory for Crop Genetics and Germplasm 12 

Enhancement, Nanjing Agricultural University, Nanjing 210095, China. † These authors 13 

contributed equally to this work. 14 

* Correspondence: [email protected]. 15 

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Abstract Traits such as grain shape, panicle length and seed shattering, play 36 

important roles in grain yield and harvest. In this study, the cloning and functional 37 

analysis of PANICLE TRAITS 2 (PT2), a novel gene from the Indica rice Chuandali 38 

(CDL), is reported. PT2 is synonymous with Growth-Regulating Factor 4 (OsGRF4), 39 

which encodes a growth-regulating factor that positively regulates grain shape and 40 

panicle length and negatively regulates seed shattering. Higher expression of OsGRF4 41 

is correlated with larger grain, longer panicle and lower seed shattering. A unique 42 

OsGRF4 mutation, which occurs at the OsmiRNA396 target site of OsGRF4, seems to 43 

be associated with high levels of OsGRF4 expression, and results in phenotypic 44 

difference. Further research showed that OsGRF4 regulated two cytokinin 45 

dehydrogenase precursor genes (CKX5 and CKX1) resulting in increased cytokinin 46 

levels, which might affect the panicle traits. High storage capacity and moderate seed 47 

shattering of OsGRF4 may be useful in high-yield breeding and mechanized 48 

harvesting of rice. Our findings provide additional insight into the molecular basis of 49 

panicle growth. 50 

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Keywords: High-yield breeding; mechanized harvesting; OsmiRNA396; panicle traits; 52 

plant growth regulator 53 

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INTRODUCTION 65 

Grain shape, panicle length and seed shattering, play important roles in grain yield, 66 

grain quality and harvesting. A few genes controlling grain size have been cloned over 67 

the past decades. For example, Grain Length 7 (GL7) encodes a 68 

TONNEAU1-recruiting motif protein. Up-regulation of GL7 expression results in 69 

longer grain length and narrower width (Wang et al. 2015a). Grain Weight 8 (GW8) 70 

encodes a protein that is a positive regulator of cell proliferation, and enhances grain 71 

width and yield in rice (Wang et al. 2012). GW8 binds directly to the Grain Width 7 72 

(GW7) promoter and represses its expression (Wang et al. 2015b). Grain Weight 2 73 

(GW2) encodes a previously unknown RING-type protein with E3 ubiquitin ligase 74 

activity. The loss of GW2 function enhances grain width, weight and yield (Song et al. 75 

2007). 76 

Genes controlling the number of spikelets in the panicle were isolated. Grain 77 

Number 1a (GN1a) encodes cytokinin oxidase/dehydrogenase 2 (OsCKX2) that 78 

degrades the phytohormone cytokinin. Reducing the expression of OsCKX2 causes 79 

cytokinin accumulation in inflorescence meristems and increases the number of 80 

spikelets per panicle (Ashikari et al. 2005). ERECT PANICLE 3/LARGER 81 

PANICLE (EP3/LP) encodes a Kelch repeat-containing F-box protein, which 82 

modulates cytokinin levels in plant tissues, regulates the inflorescence branches and 83 

the number of spikelets per panicle (Li et al. 2011b). The QTL for erect panicle on 84 

chromosome 9/DENSE AND ERECT PANICLE 1/DENSE PANICLE 1 85 

(qPE9-1/DEP1/DN1) encodes a protein homologous to the keratin-associated protein 86 

5-4 family, which regulates panicle, grain length and grain weight. The 87 

loss-of-function mutation of qPE9-1 leads to more erect panicles (Huang et al. 2009; 88 

Zhou et al. 2009; Taguchi-Shiobara et al. 2011). In fact, many panicle trait genes are 89 

pleiotropic. For example, Ghd7.1 (Yan et al. 2013) and Ghd8 (Yan et al. 2011) control 90 

the number of spikelets, affecting the plant height and heading date. 91 

Several genes determining seed shattering were characterized. 92 

Shattering1/Shattering4 (SHA1/SH4) encodes a member of the trihelix family of 93 

plant-specific transcription factors. Wild rice disperses seeds freely at maturity, unlike 94 

the domesticated rice cultivars that have lost the ability to shed their seeds at maturity 95 

because of a single amino acid substitution (Lin et al. 2007). The qSH1 (QTL of seed 96 

shattering in chromosome 1) encodes a BEL1-type homeobox gene. It represents a 97 

single-nucleotide polymorphism (SNP) causing loss of seed shattering owing to the 98 

absence of abscission layer formation (Konishi et al. 2006; Zhang et al. 2009). 99 

SHATTERING ABORTION1 (SHAT1) encodes an APETALA2 transcription factor, 100 

which is required for seed shattering via abscission zone (AZ) development in rice, 101 

positively regulated by the trihelix transcription factor SH4. The qSH1 acts 102 

downstream of SHAT1 and SH4 (Zhou et al. 2012). Shattering5 (SH5) is highly 103 

homologous to qSH1, which induces the expression of SHAT1 and Sh4 (Yoon et al. 104 

2014). During mechanical harvest, high seed shattering leads to increased loss of 105 

production. 106 

Although the genes affecting panicle traits were cloned, the molecular basis of 107 

panicle growth is still unclear. In this study, we cloned and functionally analyzed 108 

OsGRF4, an allele that shows extraordinary effect on rice panicle traits. Evidence 109 

suggests that OsGRF4 is down-regulated by miR396 during grain development. 110 

OsGRF4 from CDL carries a mutation in the coding sequence targeted by 111 

OsmiRNA396, which enhances the expression levels of OsGRF4, and results in 112 

increased grain length, grain width, grain weight, panicle length and reduced seed 113 

shattering. Based on our findings, OsGRF4 can be used in breeding new varieties to 114 

improve rice grain yield and the seed shattering. 115 

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RESULTS 117 

Map-based cloning of PT2 118 

We constructed a recombinant inbred line (RIL) and a nearly isogenic line (NIL) 119 

population from a cross between cultivar R1126 (medium-grain) and CDL (big-grain). 120 

High-resolution mapping with homozygous recombinant plants was carried out. The 121 

PT2-containing region was delimited to ~33.2 kb between the markers GL2-35-1 and 122 

GL2-12 in the long arm of rice chromosome 2 (Zhang et al. 2013). In this candidate 123 

genomic region, there were three predicted gene loci (LOC_Os02g47280, 124 

LOC_Os02g47290 and LOC_Os02g47300) according to the Rice Annotation Project 125 

(Kawahara et al. 2013). LOC_Os02g 47280 encodes a putative growth-regulating 126 

factor OsGRF4, which belongs to the GRF protein family. The GRF protein family 127 

contains two conservative domains: WRC (Trp, Arg, Cys) and QLQ (Gln, Leu, Gln), 128 

which mediate DNA binding and protein interaction, respectively (Kim et al. 2003). 129 

Previous studies have shown that the members of this family regulate rice growth, 130 

heading stage, seed development and resistance (Esther et al. 2000; Ye et al. 2004; 131 

Luo et al. 2005; Gao et al. 2010), as well as growth of cotyledons, leaves and pistil in 132 

Arabidopsis (Kim et al. 2003). LOC_Os02g47290 and LOC_Os02g47300 encode a 133 

putative uncharacterized protein, without any gene ontology. Therefore, OsGRF4 is 134 

the most probable candidate gene to PT2. 135 

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Confirmation of OsGRF4 as PT2 137 

To determine whether OsGRF4 represented the PT2, we generated transgenic plants 138 

expressing OsGRF4 (CDL) in the NIL-pt2. We introduced the plasmid carrying 139 

OsGRF4 (CDL) (designated gPT2), which contained a 4.07-kb genomic DNA 140 

fragment into NIL-pt2, driven by the ubiquitin promoter. A total of 28 putative 141 

transgenic plants (T0) were generated, and their genotypes were determined by 142 

polymerase chain reaction (PCR) amplification of the hygromycin phosphotransferase 143 

gene, of which 18 were positive transgenic lines, whereas the other 10 were negative. 144 

We observed an increase in grain size, 1000-grain weight, panicle length and changes 145 

in seed shattering of the positive-transgenic plants (T1), compared with the negative 146 

plants, without affecting the plant morphology. In contrast, the OsGRF4 RNA 147 

interference (RNAi) transgenic plants in the NIL-PT2 background generated medium 148 

grains with easy seed shattering (Figures 1, 2). A comparison of relative expression of 149 

the OsGRF4 gene overexpression and RNAi transgenic plants (T1) showed that plants 150 

with higher OsGRF4 expression levels produced bigger and heavier grains (Figure 2). 151 

Therefore, OsGRF4 represents the gene PT2. 152 

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Sequence differences in OsGRF4 154 

The full-length complementary DNA (cDNA) of OsGRF4 was isolated by reverse 155 

transcription-PCR (RT-PCR) from R1126 and CDL. Alignment of the cDNA 156 

sequence with the genomic sequence of Nipponbare indicated that OsGRF4 consists 157 

of six exons in R1126 and five exons in CDL (Figure 3). We compared the genomic 158 

sequences corresponding to the open reading frame (ORF) and the promoter regions 159 

of OsGRF4 between R1126 and CDL, and found that the coding sequence of CDL 160 

was 1,185 bp in length, encoding a predicted polypeptide of 394 amino acids, whereas 161 

the coding sequence of R1126 was 1,140 bp, encoding a polypeptide of 379 amino 162 

acids (Figure S1). There were 6 nucleotide differences in the coding sequences 163 

between R1126 and CDL, resulting in the substitution of 3 amino acids (Figure 3). 164 

The OsGRF4 gene contains a MicroRNA396 target sequence in the coding region, 165 

with two variable bases (AA - TC) between the target sequence of R1126 and CDL. 166 

The GRF4 gene is repressed by elevated levels of MicroRNA396 (Jones-Rhoades and 167 

Bartel 2004). A comparison of the promoter sequences revealed 20 polymorphisms in 168 

the 2-kb region upstream of the translation starting site, including substitutions, 169 

deletions and insertions (Figures 3, S2). 170 

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Expression of OsGRF4 in NILs 172 

We compared the expression profiles of OsGRF4 in various organs of NILs by 173 

quantitative RT-PCR analysis with total RNA. The OsGRF4 transcript levels varied 174 

drastically among the tissues. OsGRF4 was preferentially expressed in developing 175 

panicles, and the highest levels of expression were found in panicles of 7 cm in length. 176 

On the other hand, there was less transcript accumulation in the rice hull, root, stem 177 

and leaf sheath. In particular, the transcript was much more abundant in NIL-OsGRF4 178 

than in NIL-Osgrf4 in the young panicles measuring 1 cm, 4 cm, 7 cm, 11 cm and 15 179 

cm in length (Figure 4A). The differences corresponded with the critical stages of 180 

panicle traits. The OsGRF4 effect on panicle traits might be attributed to differences 181 

in expression levels. 182 

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Sequence polymorphisms of OsGRF4 in rice germplasm 184 

Twenty-five rice germplasms with abundant diversity in grain shape were selected for 185 

sequencing promoter regions and coding sequences that cover the four mutation sites 186 

in the exon of OsGRF4, and measured the grain length in a total of 25 rice accessions 187 

(Tables 1, S1). The coding sequence of the cultivated varieties was divided into two 188 

basic haplotypes: Indica-type and Japonica-type. The OsGRF4 of most Indica 189 

varieties belongs to Indica-type and the OsGRF4 of most Japonica varieties represents 190 

the Japonica-type. Some varieties, such as R1126 and R299, are Indica varieties but 191 

their OsGRF4 belongs to Japonica-type. These varieties are usually produced from 192 

interspecies crosses between Indica and Japonica. The OsGRF4 of CDL belongs to 193 

Indica-type, but an unusual mutation (AA - TC) occurred between the CDL and 194 

Indica-type. Similar types as OsGRF4 were not found within the 25 rice accessions 195 

and the database (http://ricevarmap.ncpgr.cn/) involved over thousand varieties. 196 

Therefore, the OsGRF4 of CDL was unique. The distinct mutation at the 197 

OsmiRNA396 target site of OsGRF4 may enhance the expression of OsGRF4, and 198 

result in improved grain shape, panicle length and seed shattering. 199 

The promoter sequence of the cultivated varieties represents a wide diversity, and 200 

comprises six haplotypes: CDL, Gang 46B, R700, Fengyuan B, R1126 and R299 201 

types. Six varieties (Yuzhenxiang, Yuzhuxiang, Nongxiang 18, Xiangwanxian17, 202 

Nongxiang 21 and Nongxiang 29) of CDL type represent good quality rice with long 203 

and narrow grain. OsGRF4 may not be an important gene contributing to the long 204 

grain of the six varieties. 205 

To determine the specific mutation or promoter regions of OsGRF4 responsible 206 

for the phenotypic variation, we expressed the cDNA of OsGRF4 from Nongxiang 18 207 

(Indica-type) and R1126 (Japonica-type) respectively, driven by the promoter of CDL. 208 

A total of 39 transgenic plants were obtained from pOsGRF4CDL::OsGRF4IcDNA, of 209 

which 22 were transgene positive, whereas the other 17 were negative. Forty-one 210 

transgenic plants were obtained from pOsGRF4CDL::OsGRF4JcDNA, of which 36 were 211 

transgene positive, whereas the other 5 were negative. We observed no increase in 212 

grain length in the transgene-positive plants, compared with the NIL-Osgrf4 (Table 213 

S2). This result showed that the polymorphisms in the OsGRF4 promoter region may 214 

not be responsible for the phenotypic variation. Collectively, the results from the 215 

sequencing, expression pattern and transformation studies suggest that the specific 216 

mutations in the OsGRF4 coding sequence may determine the grain shape, panicle 217 

length and seed shattering. 218 

219 

Biological roles and characterization of OsGRF4 220 

We also examined the inner and outer surfaces of glumes between NILs using a 221 

scanning electron microscope (Figure 4B–E). The cell length of glume inner surface 222 

in NIL-OsGRF4 was much longer than in NIL-Osgrf4 (Figure 4F). In addition, the 223 

cell number of glume inner surface in NIL-OsGRF4 was also higher than in 224 

NIL-Osgrf4, although differences were not significant (Figure 4G). Therefore, it is 225 

very likely that OsGRF4 positively regulated grain size mainly by increasing cell 226 

length partially and cell number, leading to enhanced longitudinal growth in the grain. 227 

The anatomical structure of the abscission zone in rice pedicels was investigated 228 

by optical microscopy (Figure S3). NIL-OsGRF4 had a partially developed abscission 229 

zone, but NIL-Osgrf4 showed a well-developed abscission zone, indicating that 230 

OsGRF4 gene improved seed shattering via differential abscission zone formation. 231 

Large spikelet hulls are associated with incomplete grain filling (Song et al. 232 

2007). Therefore, the NILs for grain filling rate were compared by measuring the 233 

fresh and dry weight of the grains during grain filling (Figure S4). Both fresh and dry 234 

weights of NIL-OsGRF4 were significantly higher (P < 0.01) than those of 235 

NIL-Osgrf4 at day 1 after fertilization, and the differences peaked at ~10 d after 236 

fertilization, when dry weights of the grains of NIL-OsGRF4 were 59.69% higher 237 

than that of NIL-Osgrf4. Thus, the increase in grain weight and yield per plant 238 

resulted from increase in both grain shape and grain filling rate. 239 

To determine the sub-cellular localization of OsGRF4, the coding sequence of 240 

OsGRF4 was fused with yellow fluorescent protein (YFP). In contrast, Ghd7, which is 241 

a nuclear protein, was fused with cyan fluorescent protein (CFP). Both fluorescent 242 

proteins were individually driven by the constitutive 35S cauliflower mosaic virus 243 

promoter. The constructs were co-transfected into rice protoplasts of etiolated 244 

seedlings by polyethylene glycol. The result showed that OsGRF4 co-localized to the 245 

nucleus with Ghd7 (Figure 5). 246 

247 

OsGRF4 genetically regulates cytokinins, cell cycle and panicle traits 248 

We analyzed the expression of 25 genes involved in cell cycle (14 putatively involved 249 

in the G1/S and 11 in the G2/M phase), 13 panicle trait-related genes and 3 genes in 250 

the cytokinin biosynthesis. The transcription levels of 6 cell cycle genes (MAD2, 251 

MCM4, CYCB2.1, CYCIaZm, CDKB, and KN) and 2 panicle trait genes, Grain Size 5 252 

(GS5) and Gn1a, were greatly elevated in NIL-OsGRF4 when compared with 253 

NIL-Osgrf4 plants (Figure 6A–C). In contrast, the expression of 2 cell cycle genes 254 

(CAK1 and CYCT1) and 2 cytokinin-related genes (CKX5 and CKX1) was 255 

significantly reduced in the NIL-OsGRF4 plants, relative to NIL-Osgrf4 plants 256 

(Figure 6A, D). 257 

Hormones play important roles in the formation of panicle architecture, especially 258 

cytokinin. Cytokinin regulates cell growth and development. The cytokinin content 259 

regulates rice grain production (Ashikari et al. 2005). The possible contribution of 260 

cytokinins to the bigger grains in NIL-OsGRF4 was determined by monitoring their 261 

levels using 7 cm young panicles of NILs. We found that the 4 kinds of cytokinins 262 

(isopentenyladenine riboside, trans-zeatin-riboside, cis-zeatin and cis-zeatin-riboside) 263 

showed significant differences between the two OsGRF4 alleles (Table 2). The high 264 

levels of cytokinin regulated by cytokinin-related genes might result in larger grain, 265 

longer panicle and lower seed shattering. 266 

267 

OsGRF4 enhances rice storage capacity and improves seed shattering 268 

To test whether OsGRF4 affects grain yield, we investigated the effects of OsGRF4 269 

on grain shape, 1000-grain weight, panicle length and seed shattering. Compared with 270 

NIL-Osgrf4, the grains of NIL-OsGRF4 were 12.23% wider and 34.32% heavier 271 

leading to a 30.37% increase in storage capacity per plant. It was also discovered that 272 

the panicle length, primary branch number and seed setting percentage showed 273 

significant differences between NILs. No significant differences were detected in 274 

other agronomic traits (Table 3), and the plant type of NIL-Osgrf4 was similar to 275 

NIL-OsGRF4 (Figure 7A-C). Interestingly, seeds of NIL-Osgrf4 were easier to thresh 276 

than those of NIL-OsGRF4. To test the shattering degree of NIL seeds, we measured 277 

the breaking tensile strength (BTS), which was inversely proportional to shattering 278 

degree. The Student’s T-test showed significant differences (P < 0.05) in the pulling 279 

strength between NILs in three different periods (Figure 7D-F). These results showed 280 

that the shattering degree in NIL-OsGRF4 was significantly harder than in 281 

NIL-Osgrf4. Since the storage capacity was the basis of yield, and medium seed 282 

shattering reduced the loss during mechanized harvesting, the OsGRF4 was very 283 

useful in breeding high-yield rice and mechanized harvesting. 284 

285 

DISCUSSION 286 

Panicle traits controlled by quantitative trait loci (QTLs) are complex yield 287 

determinants in rice. The molecular mechanisms underlying panicle traits are still 288 

unclear. Therefore, identification of QTLs that regulate panicle traits and 289 

characterization of the underlying genes enhance our understanding of rice panicle 290 

development. In this study, we reported OsGRF4 as a novel gene controlling grain 291 

shape, panicle length and rice seed shattering. The functional characterization of 292 

OsGRF4 provides a novel insight into the mechanisms controlling panicle traits. We 293 

identified the sequence differences in both the promoter region and coding sequence 294 

between R1126 and CDL. Expression of OsGRF4IcDNA or OsGRF4JcDNA driven by the 295 

CDL promoter revealed no changes in grain length, which indicates that the coding 296 

sequence targeted by OsmiRNA396 in CDL may be responsible for phenotypic 297 

variation. It was shown that OsGRF4 is down-regulated by miR396 during grain 298 

development in rice (Lan et al. 2012). Specific OsGRF4 mutations may resist the 299 

regulation by OsmiRNA396, leading to enhanced OsGRF4 expression levels, and 300 

resulting in increased grain shape, panicle length and reduced seed shattering. It was 301 

reported that OsGRF4 control grain size by activating brassinosteroid responses (Che 302 

et al. 2015), and a rare mutation in OsGRF4 affecting the binding site of OsmiR396 303 

results in large grains (Duan et al. 2015; Hu et al. 2015). A point mutation in 304 

OsSPL14 disrupts OsmiR156-directed regulation of SQUAMOSA PROMOTER 305 

BINDING PROTEIN-LIKE 14 (OsSPL14), and higher expression of OsSPL14 in the 306 

reproductive stage promotes panicle branching and higher grain yield in rice (Jiao et 307 

al. 2010; Miura et al. 2010). The regulation of OsGRF4 by microRNA may be similar 308 

to OsSPL14, which requires further investigation. 309 

There are three types of molecular mechanisms affecting phenotypic variation in 310 

the cloned genes that control grain size. The first mechanism is negative regulation of 311 

grain size. An early stop codon from a substitution in the exon of Grain Size 3 (GS3) 312 

results in large grains. GS3 acts as a negative regulator of grain size (Fan et al. 2006). 313 

Deletion of 1-bp in THOUSAND-GRAIN WEIGHT 6 (TGW6) exon results in a 314 

premature stop codon, and the functional loss of TGW6 increases grain weight and 315 

yield (Ishimaru et al. 2013) as well as grain enlargement, which is true for GW2, QTL 316 

for seed width on chromosome 5/Grain Weight 5 (qSW5/GW5) and QTL for Grain 317 

Length 3/Grain Length 3.1 (qGL3/GL3.1) (Song et al. 2007; Shomura et al. 2008; 318 

Weng et al. 2008; Zhang et al. 2012). Promoter region variation is another kind 319 

of natural mutation. It is reported that GS5 regulates the grain size via polymorphisms 320 

in the promoter region, and higher expression of GS5 results in larger grains, 321 

suggesting that GS5 positively regulates grain shape (Li et al. 2011a). Similarly, GW8 322 

affects grain size due to a critical polymorphism in the promoter region (Wang et al. 323 

2012). As a positive regulator of the traits, increased Grain Weight 6a (GW6a) 324 

expression enhances grain weight and yield (Song et al. 2015). Copy number variants 325 

(CNVs) contribute to phenotypic variation of various traits. A CNV on Grain Length 326 

on Chromosome 7 (GL7) locus contributes to diversity in grain size in rice (Wang et al. 327 

2015). Our findings provide a new molecular mechanism controlling grain shape, 328 

panicle length and seed shattering. We also found that GS5 and Gn1a were greatly 329 

elevated in NIL-OsGRF4 plants when compared with NIL-Osgrf4. Studies 330 

investigating OsGRF4 regulation of the specific genes will facilitate our 331 

understanding of the regulatory network of genes encoding panicle traits. 332 

The unusual mutation of OsGRF4 in CDL was not found in more than 20 rice 333 

cultivars sequenced in this study and over 1,000 varieties in the database, which 334 

indicates that the allele has not been used in rice breeding. OsGRF4 in CDL is a new 335 

untapped genetic resource. As a pleiotropic gene, it not only significantly increases 336 

rice storage capacity, but also decreases seed shattering. Such agronomic traits are 337 

strongly desirable in rice breeding. However, the substantial increase in grain width 338 

leads to deterioration in the quality of rice morphologically, while increasing grain 339 

length reduces head rice rate. Therefore, we propose three ways to utilize OsGRF4 340 

gene: breeding specific high-yielding rice cultivars to produce rice flour, beer and so 341 

on; gene polymerization to reduce grain width and cultivate high-yield and 342 

high-quality rice with extra-long grain; polymerizing small grains, narrow grains or 343 

special genes to breed sterile lines with small grains, and crossbreeding the sterile 344 

lines with long and thin grain restorer lines containing large grain gene OsGRF4 to 345 

obtain high yield and good quality rice with thousand-grain weight in 30-35 g. 346 

Mechanization of rice hybrid seed production based on grain length differences 347 

between sterile lines and restorer lines can also be accomplished concurrently. 348 

349 

MATERIALS AND METHODS 350 

Field planting and grain shape measurement 351 

Harvested rice grains were air-dried and stored at room temperature for at least 3 352 

months before testing. Fully-filled grains were used for measuring grain width, length 353 

and weight. Ten randomly chosen grains from each plant were assembled along a 354 

vernier caliper to measure grain width and length. Grain weight was calculated based 355 

on 200 grains and converted to 1,000-grain weight. 356 

357 

Characterization of shattering degree phenotype 358 

In order to evaluate the shattering degree of NIL-OsGRF4 and NIL-Osgrf4 359 

phenotypes, three panicles from the main stem of each plant were harvested at 20, 30 360 

and 40 days after full heading, respectively. The breaking tensile strength (BTS) upon 361 

detachment of grain from the pedicels by hand pulling was measured using a digital 362 

force gauge (Qin et al. 2010). In an individual plant, 20 grains on the uppermost part 363 

of each panicle were measured. 364 

365 

Vector construction and transformation 366 

The full-length genomic DNA of OsGRF4 was isolated by PCR with primer 367 

1390DL-1 from CDL, and then subcloned into the pCUbi1390 binary vector. The 368 

gene fragment was driven by ubiquitin promoter and the resultant plasmid was 369 

introduced into NIL-pt2 by means of Agrobacterium tumefaciens-mediated 370 

transformation (Hiei et al. 1994). The genotype of transgenic plants was determined 371 

by PCR amplification of the hygromycin phosphotransferase gene (hpt) and the 372 

analysis of hygromycin resistance. 373 

For OsGRF4-RNAi constructs, a 290 bp fragment was isolated by PCR from 374 

vector pNW55 with the following primers: I miR-s 375 

(agtaaaacgttgacatctcccttcaggagattcagtttga), II miR-a 376 

(tgaagggagatgtcaacgttttactgctgctgctacagcc), III miR*s 377 

(ctaagggtgatctcaacgttttattcctgctgctaggctg) and IV miR*a 378 

(aataaaacgttgagatcacccttagagaggcaaaagtgaa). This fragment was cloned into the plant 379 

RNAi vector pCUbi1390. The resultant plasmid was introduced into NIL-PT2. 380 

The chimeric construct (pOsGRF4CDL::OsGRF4IcDNA and 381 

pOsGRF4CDL::OsGRF4JcDNA ) was prepared in which the 2-kb promoter fragment of 382 

OsGRF4 from CDL was fused with the cDNA from Nongxiang 18, containing a 383 

coding sequence belonging to the Indica-type (IcDNA), and R1126 whose coding 384 

sequence belonged to the Japonica-type (JcDNA), respectively. The promoter 385 

fragment was ligated with the cDNA from Nongxiang 18 and R1126, respectively, 386 

and then inserted into the pCUbi1390 binary vector. The constructs were transferred 387 

into NIL-Osgrf4 by Agrobacterium tumefaciens-mediated transformation (Hiei et al. 388 

1994). 389 

390 

Expression analysis 391 

Total RNA was extracted from various rice tissues using TRIzol reagent (Invitrogen) 392 

and was reverse transcribed using the TransScript All-in-One First-Strand cDNA 393 

Synthesis SuperMix for quantitative PCR (qPCR) kit (TransGen Biotech), following 394 

the manufacturer’s instructions. RT-PCR was performed according to Jiang et al. 395 

(2007). All assays were repeated at least three times, and Ubiquitin 5 (UBQ5) was 396 

used as a reference. The relative expression was analyzed according to Schmittgen et 397 

al. (2008). Relevant PCR primers sequences are listed in Tables S3, S4. The qPCR 398 

primers involved in cell cycle were selected from the previously reported work (Li et 399 

al. 2011a). 400 

401 

Histological observation 402 

Observation of the rice glume traits: The spikelets of NIL-OsGRF4 and NIL-Osgrf4 at 403 

mature stage were collected and treated with 2.5% (vol/vol) glutaraldehyde solution, 404 

vacuumed three times, and fixed for 24 h as described by Ray (1988) _ENREF_21. The 405 

inner and outer surfaces of glumes of the spikelets were observed with a scanning 406 

electron microscope S-3000N at an accelerating voltage of 7 kV. Observation of the 407 

rice abscission zone: Panicles were harvested about 30 to 40 days after heading. The 408 

abscission zone of the pedicel was investigated as described by Ji et al. (2006) using 409 

an optical microscope after staining with Fast Green FCF and Safranine. 410 

411 

Sub-cellular localization of OsGRF4 412 

The coding sequence of OsGRF4 (CDL) was fused with PM999–YFP. The fusion 413 

protein with the insertion in the right direction was co-transfected into rice protoplasts 414 

with Ghd7:CFP as described by Zhou et al. (2009) with minor modifications. The 415 

fluorescent image was obtained using a confocal microscope (Leica, Germany) after 416 

incubating the transformed cells in the dark at 28°C for 20 h. 417 

418 

ACKNOWLEDGMENTS 419 

We thank Professor Yingguo Zhu (Wuhan University) and Doctor Changchun Yu for 420 

helping with vector construction. We are grateful to Professor Yongzhong Xing 421 

(Huazhong Agricultural University) for providing the Ghd7-CFP vector. This work 422 

was supported by National Natural Science Foundation of China (31571259), 423 

National High Technology Research and Development Program of China 424 

(2011AA10A101). 425 

426 

AUTHOR CONTRIBUTIONS 427 

H. D. and L. Y. designed the study. P. S., W. Z., Y. W., Q. H., F. S., H. L., J. W. and J. 428 

W. performed the experiments. P. S. and W. Z. analyzed the data and wrote the 429 

manuscript. 430 

431 

432 

433 

434 

435 

436 

437 

438 

439 

440 

441 

442 

443 

444 

445 

446 

447 

448 

449 

450 

451 

452 

453 

454 

455 

456 

457 

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SUPPORTING INFORMATION 607 

608 

Figure S1. The predicted protein sequences of the two OsGRF4 alleles 609 

Variant amino acids between the two parents are in green and red color 610 

611 

Figure S2. DNA sequences of the 2-kb promoter region of OsGRF4 between the two 612 

parents R1126 and CDL 613 

Variant SNPs and InDels between the two types are in red or green color 614 

615 

Figure S3. Longitudinal sections of abscission zone in grain pedicel tissues 616 

(A, B) NIL-OsGRF4. (C, D) NIL-Osgrf4. (A, C): ×100 magnification. (B, D): ×400 617 

magnification. F, flower side; P, pedicel side; AZ, abscission zone. 618 

619 

Figure S4. Time-course of grain weight between NIL-OsGRF4 and NIL-Osgrf4 620 

plants (n = 60 grains for each point) 621 

622 

Table S1. Genomic polymorphisms of OsGRF4 promoter area in 25 accessions 623 

624 

Table S2. Grain length (mm) of transgenic plants and NIL-Osgrf4 625 

626 

Table S3. Primers used for sequencing, cloning and qPCR of OsGRF4 627 

628 

Table S4. Primer sets used for qRT-PCR of the 16 genes involved in panicle traits 629 

and cytokinins 630 

631 

632 

633 

634 

635 

636 

637 

638 

639 

640 

641 

642 

Figure legends: 643 

Figure 1. Comparison of panicle traits in transgenic plants 644 

(A) Grains of OX (+) and OX (–), Scale bar = 10 mm. (B) Grains of RNAi (+) and 645 

RNAi (−), Scale bar =10 mm. (C) Panicles of OX (+) and OX (−), Scale bar = 10 cm. 646 

(D) Panicles of RNAi (+) and RNAi (−), Scale bar = 10 cm. OX, overexpression; 647 

RNAi, RNA interference; (+) indicates positive transgenic T1 plants; (−) indicates 648 

negative transgenic T1 plants. 649 

650 

Figure 2. Comparisons of panicle traits, shattering degree, tiller number and 651 

relative expression of OsGRF4 in transgenic plants 652 

(A) Grain length. (B) Grain width. (C) Setting percentage. (D) Panicle length. (E) 653 

BTS. (F) Thousand seed weight. (G) 7 cm young panicles. (H) Flag leaf. Data 654 

presented as mean ± SD (n=6 plants). A Student’s t-test was used to generate the P 655 

values. OX, overexpression; RNAi, RNA interference; (+) indicates 656 

transgenic-positive T1 plants, (−) indicates transgenic-negative T1 plants. 657 

658 

Figure 3. OsGRF4 gene structure and natural variation in alleles from R1126 659 

and CDL 660 

Cyan blocks indicate exons; thin yellow lines indicate introns; thick magenta lines 661 

indicate promoter; “ATG” and “TGA” represent translation initiation codon and 662 

termination codon, respectively. 663 

664 

Figure 4. Comparison of OsGRF4 expression pattern and glume traits in NILs 665 

(A) RH2, RH4 and RH7 represent rice hulls at reproductive stage in 2-cm, 4-cm and 666 

7-cm spikelet; 1YP, 4YP, 7YP, 11YP and 15YP are young panicles measuring 1 cm, 4 667 

cm, 7 cm, 11 cm and 15 cm length; R, S, FL and LS represent root, stem, flag leaf and 668 

leaf sheath at vegetative stage (VS) and reproductive stage (RS). All data are based on 669 

experiments in duplicate and expressed as means ± SD. Scanning electron microscopy 670 

analysis of glume inner (B, C) and outer (D, E) surfaces of NILs spikelets at mature 671 

stage. Scale bars =100 μM. Cell length (F) and cell number (G) of glume inner 672 

surfaces of NILs spikelets at mature stage. 673 

674 

Figure 5. Subcellular localization of OsGRF4 675 

Rice protoplasts were co-transformed with fusion constructs 35s::OsGRF4:YFP (A) 676 

and 35s::Ghd7:CFP (B); The merged image (C) and bright field image (D). 677 

Scale bar = 10 μm. 678 

679 

Figure 6. Effect of OsGRF4 on genes expressed in cell cycle, panicle traits and 680 

cytokinins 681 

(A) Cell cycle genes. (B, C) Panicle trait genes. (D) Cytokinins genes. The analysis of 682 

relative expression ratios was determined by qRT-PCR using 7-cm young panicles. All 683 

data are expressed as means ± SD based on experiments in triplicate. * indicated 684 

significantly different (Student’s t-test, P < 0.05). 685 

686 

Figure 7. Comparison of panicle traits and plant types in NIL-OsGRF4 and 687 

NIL-Osgrf4 plants 688 

(A) Grains of NILs. Scale bar =10 mm. (B) Panicles of NILs. Scale bar = 10 cm. (C) 689 

Plants of NILs. Scale bar =10 cm. (D) 40 days after full heading. (E) 30 days after full 690 

heading. (F) 20 days after full heading. The corresponding BST values were measured 691 

by force gauge and expressed as mean ± SD (n=3). A Student’s t-test was used to 692 

generate the P values. 693 

694 

695 

696 

697 

698 

699 

700 

701 

702 

703 

704 

705 

706 

Table 1. Genomic polymorphisms of OsGRF4 coding sequence and promoter 707 

haplotypes 708 

Coding sequence Accessions Class

Grain length (mm) SNP1 SNP2 SNP3 SNP4

Promoter haplotype

CDL Indica 13.52 A TT AA T CDL type

NIL-OsGRF4 Indica 12.67 A TT AA T CDL type

Nongxiang 99 Indica 11.52 A TT TC T CDL type

Yuzhenxiang Indica 13.28 A TT TC T CDL type

Yuzhuxiang Indica 12.74 A TT TC T CDL type

Nongxiang 18 Indica 11.73 A TT TC T CDL type

Xiangwan xian17

Indica 11.60 A TT TC T CDL type

Nongxiang 21 Indica 11.74 A TT TC T CDL type

Nongxiang 29 Indica 12.46 A TT TC T CDL type

Gang 46B Indica 7.81 A TT TC T Gang 46B type

Nongxiang 16 Indica 9.37 A TT TC T Gang 46B type

BL122 Indica 8.41 A TT TC T Gang 46B type

Jiafuzhan Indica 11.46 A TT TC T Gang 46B type

Minghui 86 Indica 10.00 A TT TC T Gang 46B type

Xinyinzhan Indica 8.06 A TT TC T Gang 46B type

R700 Indica 9.31 A TT TC T R700 type

Fengyuan B Indica 9.95 A TT TC T Fengyuan B type

R1126 Indica 10.91 G GC TC G R1126 type

NIL-Osgrf4 Indica 10.49 G GC TC G R1126 type

Nanyangzhan Indica 12.42 G GC TC G R1126 type

R299 Indica 9.92 G GC TC G R299 type

02428 Japonica 7.59 G GC TC G R299 type

C418 Japonica 9.18 G GC TC G R299 type

P7144 Japonica 9.56 G GC TC G R299 type

CY016 Japonica 8.64 G GC TC G R299 type

709 

710 

711 

712 

713 

714 

Table 2. Comparison of hormone levels in NIL-OsGRF4 and NIL-Osgrf4 715 

Hormone NIL-Osgrf4 NIL-OsGRF4

N6-isopentenyladenine (iP) 0.062 ± 0.008 0.074 ± 0.007

Isopentenyladenineriboside (iPR) 0.402 ± 0.036 0.775 ± 0.033*** trans-zeatin (tZ) 0.165 ± 0.019 0.174 ± 0.021

cis-zeatin (cZ) 0.056 ± 0.007 0.106 ± 0.014** trans-zeatin-riboside (tZR) 0.299 ± 0.012 0.339 ± 0.025* cis-zeatin-riboside (cZR) 0.334 ± 0.014 0.488 ± 0.067** indole acetic acid (IAA) 47.38 ± 5.83 50.59 ± 2.05

abscisic acid (ABA) 13.28 ± 0.74 14.61 ± 1.69

The content of 8 hormones was determined by liquid chromatography-tandem mass 716 

spectrometry (LC-MS/MS) using 7-cm-long young panicles from at least 12 plants, in 717 

at least triplicates. All data were expressed as means ± SD. *, ** and *** indicated 718 

that phenotypes between NILs were significantly different (Student’s t-test, P < 0.05, 719 

0.01 and 0.001, respectively). 720 

721 

722 

723 

724 

725 

726 

727 

728 

729 

730 

731 

732 

733 

734 

735 

736 

Table 3. Grain shape and yield component traits of the two NILs 737 

Traits NIL-Osgrf4 NIL-OsGRF4

Panicle length (cm) 21.42 ± 0.51 25.54 ± 0.74***

Primary branch number 10.4 ± 0.55 11.4 ± 0.89*

Secondary branch number 19.8 ± 2.39 18.0 ± 2.45

Spikelet number per panicle 125.4 ± 6.73 126.2 ± 10.31

Grain number per panicle 119.2 ± 8.23 113.0 ± 10.77

Seed setting percentage 95.0 ± 1.88 89.47 ± 1.83***

Tiller number 6.26 ± 1.43 5.91 ± 1.87

Grain length (mm) 10.49 ± 0.26 12.67 ± 0.20***

Grain width (mm) 2.78 ± 0.13 3.12 ± 0.04***

1,000-grain weight (g) 31.7 ± 0.34 42.58 ± 1.58***

Storage capacity per plant (g) 27.82 ± 1.39 36.27 ± 3.25***

Plant height (cm) 108.68 ± 1.2 109.03 ± 1.77

All data were derived from the two NILs planted in random block design in triplicate. 738 

All data were expressed as means ± SD (n = 5 plants). * and *** indicated that 739 

phenotypes between NILs were significantly different (Student’s t-test, P < 0.05 and 740 

0.001, respectively). 741 

742 

743 

744 

745 

746 

747 

748 

749 

750 

751 

752 

753 

754 

755 

Figures: 756 

757 

758  759 

Figure 1. Comparison of panicle traits in transgenic plants 760 

(A) Grains of OX (+) and OX (–), Scale bar = 10 mm. (B) Grains of RNAi (+) and 761 

RNAi (−), Scale bar =10 mm. (C) Panicles of OX (+) and OX (−), Scale bar = 10 cm. 762 

(D) Panicles of RNAi (+) and RNAi (−), Scale bar = 10 cm. OX, overexpression; 763 

RNAi, RNA interference; (+) indicates positive transgenic T1 plants; (−) indicates 764 

negative transgenic T1 plants. 765 

766 

767 

768 

769 

770 

771 

772 

773 

774 

775 

776 

777 

778 

779 

780 

781 

782 

783 

784 

785 

786 

787 

788 

789 

790 

791 

792 

793 

794 

795 

796 

797 

798 

Figure 2. Comparisons of panicle traits, shattering degree, tiller number and 799 

relative expression of OsGRF4 in transgenic plants 800 

(A) Grain length. (B) Grain width. (C) Setting percentage. (D) Panicle length. (E) 801 

BTS. (F) Thousand seed weight. (G) 7 cm young panicles. (H) Flag leaf. Data 802 

presented as mean ± SD (n=6 plants). A Student’s t-test was used to generate the P 803 

values. OX, overexpression; RNAi, RNA interference; (+) indicates 804 

transgenic-positive T1 plants, (−) indicates transgenic-negative T1 plants. 805 

806 

807 

808 

809 

810 

811 

812 

813 

814 

815 

816 

Figure 3. OsGRF4 gene structure and natural variation in alleles from R1126 817 

and CDL 818 

Cyan blocks indicate exons; thin yellow lines indicate introns; thick magenta lines 819 

indicate promoter; “ATG” and “TGA” represent translation initiation codon and 820 

termination codon, respectively. 821 

822 

823 

824 

825 

826 

827 

828 

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Figure 4. Comparison of OsGRF4 expression pattern and glume traits in NILs 860 

(A) RH2, RH4 and RH7 represent rice hulls at reproductive stage in 2-cm, 4-cm and 861 

7-cm spikelet; 1YP, 4YP, 7YP, 11YP and 15YP are young panicles measuring 1 cm, 4 862 

cm, 7 cm, 11 cm and 15 cm length; R, S, FL and LS represent root, stem, flag leaf and 863 

leaf sheath at vegetative stage (VS) and reproductive stage (RS). All data are based on 864 

experiments in duplicate and expressed as means ± SD. Scanning electron microscopy 865 

analysis of glume inner (B, C) and outer (D, E) surfaces of NILs spikelets at mature 866 

stage. Scale bars =100 μM. Cell length (F) and cell number (G) of glume inner 867 

surfaces of NILs spikelets at mature stage. 868 

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870 

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Figure 5. Subcellular localization of OsGRF4 884 

Rice protoplasts were co-transformed with fusion constructs 35s::OsGRF4:YFP (A) 885 

and 35s::Ghd7:CFP (B); The merged image (C) and bright field image (D). 886 

Scale bar = 10 μm. 887 

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Figure 6. Effect of OsGRF4 on genes expressed in cell cycle, panicle traits and 901 

cytokinins 902 

(A) Cell cycle genes. (B, C) Panicle trait genes. (D) Cytokinins genes. The analysis of 903 

relative expression ratios was determined by qRT-PCR using 7-cm young panicles. All 904 

data are expressed as means ± SD based on experiments in triplicate. * indicated 905 

significantly different (Student’s t-test, P < 0.05). 906 

907 

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Figure 7. Comparison of panicle traits and plant types in NIL-OsGRF4 and 913 

NIL-Osgrf4 plants 914 

(A) Grains of NILs. Scale bar =10 mm. (B) Panicles of NILs. Scale bar = 10 cm. (C) 915 

Plants of NILs. Scale bar =10 cm. (D) 40 days after full heading. (E) 30 days after full 916 

heading. (F) 20 days after full heading. The corresponding BST values were measured 917 

by force gauge and expressed as mean ± SD (n=3). A Student’s t-test was used to 918 

generate the P values. 919 

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