PPARD is an Inhibitor of Cartilage Growth in External Ears

Abstract

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.

A genome-wide detection of selection signatures in conserved and commercial pig breeds maintained in Poland

“…The most interesting diversifying selection candidate in this breed seems to be PPARD gene (Peroxisome proliferator-activated receptor beta/delta) located on SSC7, which was shown to be associated both with ear morphology and backfat thickness [ 39 , 40 ]. A previous study identified a missense mutation in the PPARD gene that significantly reduces its transcription activity, and consequently causes enlarged external ears in pigs [ 40 , 41 ]. This is concordant with the phenotype of PUL breed which is the only breed with prick ear morphology in this study and the detected signal potentially results from diversifying selection for ear morphology among the studied breeds.…”

Modeling Normal and Pathological Ear Cartilage in vitro Using Somatic Stem Cells in Three-Dimensional Culture

“…Developing human fetal external ears at 16 and 22 PCW (N = 1) were analyzed by histology and immunohistochemistry on paraffin sections (Figure 1). At both 16 and 22 PCW, two zones were identified in the developing cartilage layer: (i) a central layer, highly cellularized, containing immature chondroblasts with round nuclei and a few small peri-cellular cavities, identifiable as the chondrium, and (ii) the inner perichondrium, a thin, regular layer which contained spindle-like/fibroblastic shaped cells (we define these cells as CSPCs, according to Kobayashi et al, 2011a;Jiang and Tuan, 2015;Zhang et al, 2017). In many areas of the 16 PCW ear cartilage, the inner perichondrium appeared irregular ( Figure 1A).…”

“…These cells are thought to be involved in the maintenance of tissue homeostasis. CSPCs isolated from normal ear cartilage exhibit typical features of mesenchymal stem cells (MSCs), such as adherence to plastic, spindle-like morphology and three-mesenchymal lineage differentiation potential in vitro (Kobayashi et al, 2011a;Jiang and Tuan, 2015;Zhang et al, 2017).…”

Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature

“…We have hypothesized that the skeletal abnormalities (joint laxity or dislocations) in affected individuals of family F002 could be caused by one of other two segregating variants, PPARD: p.(Glu10Ala) or LMO7: p.(Glu511Gly). PPARD has been reported to be involved in the development of cartilage (37), so it could be a good candidate for skeletal phenotypes.…”