SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium.
Activins
/ metabolism
Animals
Cell Differentiation
/ physiology
Core Binding Factor Alpha 2 Subunit
/ metabolism
Diethylstilbestrol
/ adverse effects
Epithelium
/ drug effects
Estrogens, Non-Steroidal
/ adverse effects
Female
Gene Expression Regulation, Developmental
Homeodomain Proteins
/ metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mullerian Ducts
/ drug effects
Oligonucleotide Array Sequence Analysis
Smad4 Protein
/ metabolism
Trans-Activators
/ metabolism
Uterus
/ embryology
Vagina
/ drug effects
Vaginal Diseases
/ chemically induced
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
16
02
2020
accepted:
10
06
2020
revised:
08
06
2020
pubmed:
24
6
2020
medline:
15
12
2021
entrez:
24
6
2020
Statut:
ppublish
Résumé
During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.
Identifiants
pubmed: 32572167
doi: 10.1038/s41418-020-0579-z
pii: 10.1038/s41418-020-0579-z
pmc: PMC7852590
doi:
Substances chimiques
Core Binding Factor Alpha 2 Subunit
0
Estrogens, Non-Steroidal
0
Homeodomain Proteins
0
Runx1 protein, mouse
0
Six1 protein, mouse
0
Smad4 Protein
0
Smad4 protein, mouse
0
Trans-Activators
0
Trp63 protein, mouse
0
activin A
0
Activins
104625-48-1
Diethylstilbestrol
731DCA35BT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3307-3320Subventions
Organisme : NICHD NIH HHS
ID : R01 HD064402
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA154358
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
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