TFEB Controls Syncytiotrophoblast Formation and Hormone Production in Placenta

Authors

Marcella Cesana
Gennaro Tufano
Francesco Panariello
Nicolina Zampelli
Chiara Soldati
Margherita Mutarelli
Sandro Montefusco
Giuseppina Grieco
Lucia Vittoria Sepe
Barbara Rossi
Edoardo Nusco
Giada Rossignoli
Giorgia Panebianco
Fabrizio Merciai
Emanuela Salviati
Eduardo Maria Sommella
Pietro Campiglia
Graziano Martello
Davide Cacchiarelli
Diego Luis Medina
Andrea Ballabio

Publication Date

11-1-2024

Journal

Cell Death & Differentiation

DOI

10.1038/s41418-024-01337-y

PMID

38965447

PMCID

PMC11519894

PubMedCentral® Posted Date

7-4-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Trophoblasts, Female, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Pregnancy, Placenta, Mice, Mice, Knockout, Humans, Placentation, Estradiol, Molecular biology, Cell biology

Abstract

TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of the syncytiotrophoblast layer. Indeed, using in vitro models of syncytialization, we demonstrated that TFEB translocates into the nucleus during syncytiotrophoblast formation and binds to the promoters of crucial placental genes, including genes encoding fusogenic proteins (Syncytin-1 and Syncytin-2) and enzymes involved in steroidogenic pathways, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17β-Estradiol (E2). Conversely, TFEB depletion impairs both syncytial fusion and endocrine properties of syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placental hormones and E2 production. Notably, restoration of TFEB expression resets syncytiotrophoblast identity. Our findings identify that TFEB controls placental development and function by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.