Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells.
Propagation and differentiation of stem cell populations are tightly regulated to provide sufficient cell numbers for tissue formation while maintaining the stem cell pool. Embryonic parts of the mammalian placenta are generated from differentiating trophoblast stem cells (TSCs) invading the maternal decidua. Here we demonstrate that lysine-specific demethylase 1 (Lsd1) regulates differentiation onset of TSCs. Deletion of Lsd1 in mice results in the reduction of TSC number, diminished formation of trophectoderm tissues and early embryonic lethality. Lsd1-deficient TSCs display features of differentiation initiation, including alterations of cell morphology, and increased migration and invasion. We show that increased TSC motility is mediated by the premature expression of the transcription factor Ovol2 that is directly repressed by Lsd1 in undifferentiated cells. In summary, our data demonstrate that the epigenetic modifier Lsd1 functions as a gatekeeper for the differentiation onset of TSCs, whereby differentiation-associated cell migration is controlled by the transcription factor Ovol2.
1] Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany [2].
Dongmei
D
Zhu
1] Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany [2].
Stefanie
S
Hölz
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Eric
E
Metzger
Medizinische Universitätsklinik, Abteilung Innere Medizin IV, Nephrologie, Klinikum der Universität Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
Mihael
M
Pavlovic
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Anett
A
Jandausch
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Cordula
C
Jilg
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Petra
P
Galgoczy
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Corinna
C
Herz
Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Markus
M
Moser
Department of Physiological Genetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirc 67404, France.
Daniel
D
Metzger
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany.
Thomas
T
Günther
1] Medizinische Universitätsklinik, Abteilung Innere Medizin IV, Nephrologie, Klinikum der Universität Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany [2] BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
Sebastian J
SJ
Arnold
1] Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacher Strasse 66, 79106 Freiburg, Germany [2] BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
Roland
R
Schüle
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D056466:Histone Demethylases / Q000502:physiology*; D051379:Mice; D011247:Pregnancy; D013234:Stem Cells / Q000166:cytology*; D014327:Trophoblasts / Q000166:cytology*
D056466:Histone Demethylases; C504076:KDM1a protein, mouse