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Persistent Human KIT Receptor Signaling Disposes Murine Placenta to Premature Differentiation Resulting in Severely Disrupted Placental Structure and Functionality

Authors
  • Kaiser, Franziska1
  • Hartweg, Julia1, 2
  • Jansky, Selina1, 3, 4
  • Pelusi, Natalie1, 5
  • Kubaczka, Caroline1, 6
  • Sharma, Neha1, 7
  • Nitsche, Dominik1, 8
  • Langkabel, Jan1
  • Schorle, Hubert1
  • 1 (J.L.)
  • 2 Department of Medicine II and IZKF Research Laboratory, Würzburg University Hospital, 97080 Würzburg, Germany
  • 3 Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
  • 4 Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 5 Department of Molecular Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany
  • 6 Division of Pediatric Hematology/Oncology, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
  • 7 Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
  • 8 Life & Medical Sciences-Institute (LIMES), University of Bonn, 53115 Bonn, Germany
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Jul 31, 2020
Volume
21
Issue
15
Identifiers
DOI: 10.3390/ijms21155503
PMID: 32752102
PMCID: PMC7432075
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Green

Abstract

Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of ligand binding. As the role of the KIT receptor in placental signaling cascades is poorly understood, we analyzed the impact of KITD816V expression on placental development using a humanized mouse model. Placentas from KITD816V animals present with a grossly changed morphology, displaying a reduction in labyrinth and spongiotrophoblast layer and an increase in the Parietal Trophoblast Giant Cell (P-TGC) layer. Elevated differentiation to P-TGCs was accompanied with reduced differentiation to other Trophoblast Giant Cell (TGC) subtypes and by severe decrease in proliferation. The embryos display growth retardation and die in utero. KITD816V-trophoblast stem cells (TSC) differentiate much faster compared to wild type (WT) controls. In undifferentiated KITD816V-TSCs, levels of Phosphorylated Extracellular-signal Regulated Kinase (P-ERK) and Phosphorylated Protein Kinase B (P-AKT) are comparable to wildtype cultures differentiating for 3–6 days. Accordingly, P-TGC markers Placental Lactogen 1 (PL1) and Proliferin (PLF) are upregulated as well. The results reveal that KIT signaling orchestrates the fine-tuned differentiation of the placenta, with special emphasis on P-TGC differentiation. Appropriate control of KIT receptor action is therefore essential for placental development and nourishment of the embryo.

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