The G32E Functional Variant Reduces Activity of PPARD by Nuclear Export and Post-Translational Modification in Pigs

Duan, Yanyu; Brenig, Bertram; Wu, Xiaohui; Ren, Jun; Huang, Lusheng

doi:10.1371/journal.pone.0075925

Cited by 9 publications

(19 citation statements)

References 55 publications

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“…Taken together, PPARD has an inhibitive effect on chondrogenesis in pig external ears. We have shown that the G32E causative mutation reduces activity of PPARD 9. Therefore, it is conceivable to observe that Erhualian carrying the mutant allele at the G32E site had a faster growth rate of auricular cartilage than Duroc carrying the wild-type allele at this site.…”

Section: Discussionmentioning

confidence: 93%

PPARD is an Inhibitor of Cartilage Growth in External Ears

Zhang

Duan

et al. 2017

Int. J. Biol. Sci.

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Peroxisome proliferator-activated receptor beta/delta (PPARD) is an important determinant of multiple biological processes. Our previous studies identified a missense mutation in the PPARD gene that significantly reduces its transcription activity, and consequently causes enlarged external ears in pigs. However, the mechanisms underlying the causality has remained largely unknown. Here, we show that PPARD retards the development of auricular cartilage by accelerating the apoptosis of cartilage stem/progenitor cells (CSPCs), the terminal differentiation of cartilage cells and the degradation of cartilage extracellular matrix in the auricle. At the transcription level, PPARD upregulates a set of genes that are associated with CSPCs apoptosis and chondrogenic differentiation, chondroblast differentiation and extracellular matrix degradation. ChIP-seq identified direct target genes of PPARD, including a well-documented gene for cartilage development: PPARG. We further show that compared to wild-type PPARD, the G32E mutant up-regulates the expression of PPARG and subsequently leads to the downregulation of critical genes that inhibit cartilage growth. These findings allow us to conclude that PPARD is an inhibitor of auricular cartilage growth in pigs. The causative mutation (G32E) in the PPARD gene attenuates the PPARD-mediated retardation of cartilage growth in the auricle, contributing to enlarged ears in pigs. The findings advance our understanding of the mechanisms underlying auricular development in mammals, and shed insight into the studies of innate pinna disorders and cartilage regeneration medicine in humans.

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Section: Discussionmentioning

confidence: 93%

PPARD is an Inhibitor of Cartilage Growth in External Ears

Zhang

Duan

et al. 2017

Int. J. Biol. Sci.

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“…Increasingly, it is becoming apparent that developmental signals can be fine-tuned by modulating protein stability, localization, and activity through post-translational modifications [10][11][12]. Palmitoylation is a key post-translational modification that is mediated by a family of Asp-His-HisCys (DHHC)-containing palmitoyl acyltransferases (PATs) [13,14].…”

Section: Introductionmentioning

confidence: 99%

Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

Chen

Shi

Wang

et al. 2014

Stem Cells and Development

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Neither the roles of Asp-His-His-Cys (DHHC)-containing proteins in embryonic cell fate specification are well defined, nor the underlying mechanisms of their activity are well understood. Here, we compared the embryonic function of zinc finger DHHC-type containing (Zdhhc13) in zebrafish embryos and in an in vitro cell model. Zdhhc13, a critical regulator of bone morphogenetic protein (BMP) signaling, specifically bound to Smad6 to induce its perinuclear accumulation and degradation through a mechanism independent of its palmitoyltransferase activity. We showed that Zdhhc13 played a crucial role during zebrafish embryogenesis in the control of germ layer specification, particularly in ectoderm and mesoderm differentiation homeostasis. Depletion of Zdhhc13 led to the neuralization of ectoderm and dorsalization of mesoderm in zebrafish embryos. Moreover, Zdhhc13 antagonized Smad6 during BMP-dependent signaling and early lineage decisions in our in vitro cell model. Our results extended the cellular role of Zdhhc13, suggesting that it acts as a regulator in BMP signaling, and established that the embryonic function of Zdhhc13 is in lineage specification.

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“…; Duan et al . ). Furthermore, genome fragments containing Wnt inhibitory factor 1 ( WIF1 ) and high mobility group AT‐hook 2 ( HMGA2 ) also appear to control ear size in both pigs and dogs (Jones et al .…”

Section: Mutations Identified In Wif1 and Hmga2 Genesmentioning

confidence: 97%

Molecular cloning of WIF1 and HMGA2 reveals ear‐preferential expression while uncovering a missense mutation associated with porcine ear size in WIF1

et al. 2019

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Considerable diversity exists in porcine ear size, which is an important morphological feature of pig breeds. Previously, we localized four crucial candidate genes-high mobility group AT-hook 2 (HMGA2), LEM domain-containing 3 (LEMD3), methionine sulfoxide reductase B3 (MSRB3) and Wnt inhibitory factor 1 (WIF1)-on Sus Scrofa chromosome 5 affecting porcine ear size, then cloned LEMD3 and MSBR3. In this study, we performed rapid amplification of cDNA ends to obtain full-length cDNA sequences of 2338-bp WIF1 and 2998-bp HMGA2. Using quantitative real-time PCR, we revealed that WIF1 expression was highest in ear cartilage of 60-day-old pigs and that this is therefore a better candidate gene for ear size than HMGA2. We further screened coding sequence variants in both genes and identified only one missense mutation (WIF1: c.1167C>G) in a conserved epidermal growth factor-like domain from the mammalian WIF1 protein. The protein-altering mutation was significantly associated with ear size across the Large White 9 Minzhu hybrid and Beijing Black pig populations. When WIF1:c.1167C>G was included as fixed effect in the model to re-run a genome-wide association study in the Large White 9 Minzhu intercross population the P-value of the peak SNP on SSC5 from re-running the genome-wide association study dropped from 2.45E-12 to 7.33E-05. Taken together, the WIF1:c.1167C>G could be an important mutation associated with ear size. Our findings provide helpful information for further studies of the molecular mechanisms controlling porcine ear size.

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The G32E Functional Variant Reduces Activity of PPARD by Nuclear Export and Post-Translational Modification in Pigs

Cited by 9 publications

References 55 publications

PPARD is an Inhibitor of Cartilage Growth in External Ears

PPARD is an Inhibitor of Cartilage Growth in External Ears

Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

Molecular cloning of WIF1 and HMGA2 reveals ear‐preferential expression while uncovering a missense mutation associated with porcine ear size in WIF1

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