Peroxisome proliferator‐activated receptor gamma‐ligand‐binding domain mutations associated with familial partial lipodystrophy type 3 disrupt human trophoblast fusion and fibroblast migration

Hussein Shoaito (1) , Sabine Chauveau (1) , Camille Gosseaume (2, 3, 4) , William Bourguet (5) , Corinne Vigouroux (6, 3, 2) , Camille Vatier (2, 3, 4) , Catherine Pienkowski (7) , Thierry Fournier (1) , Séverine A Degrelle (1, 8, 9)

1 3PHM - UMR-S 1139 - Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal
2 CRSA - Centre de Recherche Saint-Antoine
3 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
4 CHU Saint-Antoine [AP-HP]
5 CBS - Centre de Biologie Structurale [Montpellier]
6 SU - Sorbonne Université
7 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
8 Inovarion
9 PremUp Foundation

The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is essential for placental development, and alterations in its expression and/or activity are associated with human placental pathologies such as pre-eclampsia or IUGR. However, the molecular regulation of PPARG in cytotrophoblast differentiation and in the underlying mesenchyme remains poorly understood. Our main goal was to study the impact of mutations in the ligand-binding domain (LBD) of the PPARG gene on cytotrophoblast fusion (PPARG E352Q ) and on fibroblast cell migration (PPARG R262G /PPARG L319X ). Our results showed that, compared to cells with reconstituted PPARG WT , transfection with PPARG E352Q led to significantly lower PPARG activity and lower restoration of trophoblast fusion. Likewise, compared to PPARG WT fibroblasts, PPARG R262G /PPARG L319X fibroblasts demonstrated significantly inhibited cell migration. In conclusion, we report that single missense or nonsense mutations in the LBD of PPARG significantly inhibit cell fusion and migration processes.

Keywords: cell fusion; cell migration; familial partial lipodystrophy type 3 (FPLD3); Placenta; PPARG; trophoblast differentiation

Domains: Endocrinology and metabolism; Genomics [q-bio.GN]; Subcellular Processes [q-bio.SC]

Hussein Shoaito, Sabine Chauveau, Camille Gosseaume, William Bourguet, Corinne Vigouroux, et al.. Peroxisome proliferator‐activated receptor gamma‐ligand‐binding domain mutations associated with familial partial lipodystrophy type 3 disrupt human trophoblast fusion and fibroblast migration. Journal of Cellular and Molecular Medicine, 2020, 24 (13), pp.7660 - 7669. ⟨10.1111/jcmm.15401⟩. ⟨hal-04707143⟩