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Miranda AL, Racca AC, Kourdova LT, et al. Krüppel-like factor 6 (KLF6) requires its amino terminal domain to promote villous trophoblast cell fusion. Placenta. 2021;117:139-149doi: 10.1016/j.placenta.2021.12.006.
Miranda, A. L., Racca, A. C., Kourdova, L. T., Rojas, M. L., Cruz Del Puerto, M., Rodriguez-Lombardi, G., Salas, A. V., Travella, C., da Silva, E. C. O., de Souza, S. T., Fonseca, E. J. S., Marques, A. L. X., Borbely, A. U., Genti-Raimondi, S., & Panzetta-Dutari, G. M. (2021). Krüppel-like factor 6 (KLF6) requires its amino terminal domain to promote villous trophoblast cell fusion. Placenta, 117139-149. https://doi.org/10.1016/j.placenta.2021.12.006
Miranda, Andrea L, et al. "Krüppel-like factor 6 (KLF6) requires its amino terminal domain to promote villous trophoblast cell fusion." Placenta vol. 117 (2021): 139-149. doi: https://doi.org/10.1016/j.placenta.2021.12.006
Miranda AL, Racca AC, Kourdova LT, Rojas ML, Cruz Del Puerto M, Rodriguez-Lombardi G, Salas AV, Travella C, da Silva ECO, de Souza ST, Fonseca EJS, Marques ALX, Borbely AU, Genti-Raimondi S, Panzetta-Dutari GM. Krüppel-like factor 6 (KLF6) requires its amino terminal domain to promote villous trophoblast cell fusion. Placenta. 2021 Dec 04;117:139-149. doi: 10.1016/j.placenta.2021.12.006. Epub 2021 Dec 04. PMID: 34894601.
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Placenta. 2021 Dec 04;117:139-149. doi: 10.1016/j.placenta.2021.12.006. Epub 2021 Dec 04.

Krüppel-like factor 6 (KLF6) requires its amino terminal domain to promote villous trophoblast cell fusion.

Placenta

Andrea L Miranda, Ana C Racca, Lucille T Kourdova, Maria Laura Rojas, Mariano Cruz Del Puerto, Gonzalo Rodriguez-Lombardi, Andrea V Salas, Claudia Travella, Elaine C O da Silva, Samuel T de Souza, Eduardo J S Fonseca, Aldilane L X Marques, Alexandre U Borbely, Susana Genti-Raimondi, Graciela M Panzetta-Dutari

Affiliations

  1. Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
  2. Servicio de Ginecología y Obstetricia, Hospital Privado Universitario de Córdoba, X5000HUA, Córdoba, Argentina.
  3. Optics and Nanoscopy Group, Physics Institute, Federal University of Alagoas, Maceio, Brazil.
  4. Cell Biology Laboratory, Institute of Health and Biological Sciences, Federal University of Alagoas, Maceio, Brazil.
  5. Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina. Electronic address: [email protected].

PMID: 34894601 DOI: 10.1016/j.placenta.2021.12.006

Abstract

INTRODUCTION: Villous cytotrophoblast (vCTB) cells fuse to generate and maintain the syncytiotrophoblast layer required for placental development and function. Krüppel-like factor 6 (KLF6) is a ubiquitous transcription factor with an N-terminal acidic transactivation domain and a C-terminal zinc finger DNA-binding domain. KLF6 is highly expressed in placenta, and it is required for proper placental development. We have demonstrated that KLF6 is necessary for cell fusion in human primary vCTBs, and in the BeWo cell line.

MATERIALS AND METHODS: Full length KLF6 or a mutant lacking its N-terminal domain were expressed in BeWo cells or in primary vCTB cells isolated from human term placentas. Cell fusion, gene and protein expression, and cell proliferation were analyzed. Moreover, Raman spectroscopy and atomic force microscopy (AFM) were used to identify biochemical, topography, and elasticity cellular modifications.

RESULTS: The increase in KLF6, but not the expression of its deleted mutant, is sufficient to trigger cell fusion and to raise the expression of β-hCG, syncytin-1, the chaperone protein 78 regulated by glucose (GRP78), the ATP Binding Cassette Subfamily G Member 2 (ABCG2), and Galectin-1 (Gal-1), all molecules involved in vCTB differentiation. Raman and AFM analysis revealed that KLF6 reduces NADH level and increases cell Young's modulus. KLF6-induced differentiation correlates with p21 upregulation and decreased cell proliferation. Remarkable, p21 silencing reduces cell fusion triggered by KLF6 and the KLF6 mutant impairs syncytialization and decreases syncytin-1 and β-hCG expression.

DISCUSSION: KLF6 induces syncytialization through a mechanism that involves its regulatory transcriptional domain in a p21-dependent manner.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords: Cellular elasticity; Differentiation; KLF6; Regulatory domain; Villous trophoblast

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