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

Autor: Neha Sharma, Natalie Pelusi, Caroline Kubaczka, Hubert Schorle, Franziska Kaiser, Julia Hartweg, Dominik Nitsche, Selina Jansky, Jan Langkabel
Jazyk: angličtina
Rok vydání: 2020
Předmět:
spongiotrophoblast
Placenta
lcsh:Chemistry
Mice
Pregnancy
Placental lactogen
Receptor
lcsh:QH301-705.5
Spectroscopy
Kinase
placental development
Gene Expression Regulation
Developmental
General Medicine
embryonic growth retardation
invasion
Computer Science Applications
Cell biology
Trophoblasts
Proto-Oncogene Proteins c-kit
medicine.anatomical_structure
embryonic structures
trophoblast stem cell
Female
Stem cell
MAP Kinase Signaling System
Biology
Catalysis
Article
KITD816V
Inorganic Chemistry
Downregulation and upregulation
medicine
Animals
Humans
Neoplasm Invasiveness
premature differentiation
Physical and Theoretical Chemistry
Molecular Biology
Protein kinase B
KIT receptor
trophoblast giant cell
Organic Chemistry
Trophoblast
Placental Lactogen
Placentation
Prolactin
Homeobox A10 Proteins
lcsh:Biology (General)
lcsh:QD1-999
Proto-Oncogene Proteins c-akt
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 15
International Journal of Molecular Sciences, Vol 21, Iss 5503, p 5503 (2020)
ISSN: 1422-0067
Popis: 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&ndash
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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje