| dc.contributor.advisor | Kessel, Michael Prof. Dr. | |
| dc.contributor.author | Pirouz, Mehdi | |
| dc.date.accessioned | 2013-11-18T12:16:13Z | |
| dc.date.available | 2013-11-18T12:16:13Z | |
| dc.date.issued | 2013-11-18 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0001-BC58-8 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4150 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4150 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Mad2l2 in primordial germ cell development and pluripotency | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Engel, Wolfgang Prof. Dr. | |
| dc.date.examination | 2013-02-22 | |
| dc.description.abstracteng | The development of primordial germ cells (PGCs) involves several waves of
epigenetic reprogramming. A major step is the transition from the stably suppressive
histone modification H3K9me2 to the more flexible, still repressive H3K27me3, while
the cells are arrested in the G2 phase of their cell cycle. The significance and
underlying molecular mechanism of these events were so far unknown. In this study,
a role of the Mad2l2 (Mad2B, Rev7) gene product in development of PGCs was
investigated. Mad2l2 is a HORMA domain protein, which is involved in proteinprotein
interaction. Mad2l2 is essential for PGC, but not for somatic development.
PGCs were specified normally in Mad2l2-/- embryos, but their chromatin did not
proceed from the H3K9me2 to H3K27me3 state. Mad2l2-/- PGCs failed to arrest in
the G2 phase, and were eliminated by apoptosis. Co-immunoprecipitation analysis
showed that Mad2l2 could interact with the histone methyltransferases G9a and
GLP, and thus lead to a downregulation of H3K9me2. It also interacts physically with
Cdk1, which together with Cyclin B1 is the main driving force for mitotic entrance and
progression. The inhibitory binding of Mad2l2 to Cdk1 could arrest the cell cycle in
the G2 phase, and therefore allow the other histone methyltransferase, Ezh2, to
upregulate H3K27me3. In conclusion, Mad2l2 is essential for epigenetic
reprogramming in mouse PGCs.
Mad2l2-/- ESC lines cultured in conventional condition (LIF/Serum) showed
evidence for a spontaneous differentiation into epithelial-like cells with the molecular
characteristics of primitive endoderm. They had a cell cycle similar to that of
differentiated cells, failed to incorporate into chimeras, and deviated to primitive
endoderm at the expense of pluripotency. They also manifested an epigenetic
configuration distinct from normal ESCs, namely elevated H3K9me2 and H3K27me3
levels. Differentiating cells disappeared once the cultures were shifted to the
chemically defined medium supplemented with two inhibitors of MEK and Wnt
pathways (LIF/2i). Co-immunoprecipitation of Mad2l2 in ESCs followed by mass
spectrometry identified CETN2 as its interacting partner. This interaction might be
involved in regulation of Nanog expression and thus in sustaining self-renewal of
ESCs. Altogether, these data point to essential role of Mad2l2 in pluripotent ESCs. | de |
| dc.contributor.coReferee | Eichele, Gregor Prof. Dr. | |
| dc.subject.eng | Mad2l2, Primordial Germ Cell, Pluripotency, Cell Cycle, Epigenetic | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0001-BC58-8-9 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 771755007 | |