Advanced

Downstream effects of master regulators in two brain diseases.

Braun, Sebastian LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:64.
Abstract
In paper one, we investigated how the pharmacological activation and inhibition of the glucocorticoid system

affects lifespan and symptoms in a mouse model for RTT. We performed a long-term drug treatment study with

the GR activator corticosterone and the GR inhibitor RU486 under which we measured the lifespan and onset

of RTT-like symptoms of male Mecp2-null and female Mecp2 heterozygous mice in comparison to untreated

mutant and to treated and untreated wild-type animals. We could demonstrate that activation of the

glucocorticoid hormone system reduces the lifespan of Mecp2-/y mice and the symptom-free lifetime of

Mecp2+/- mice and that treatment with the GR inhibitor RU486 has an... (More)
In paper one, we investigated how the pharmacological activation and inhibition of the glucocorticoid system

affects lifespan and symptoms in a mouse model for RTT. We performed a long-term drug treatment study with

the GR activator corticosterone and the GR inhibitor RU486 under which we measured the lifespan and onset

of RTT-like symptoms of male Mecp2-null and female Mecp2 heterozygous mice in comparison to untreated

mutant and to treated and untreated wild-type animals. We could demonstrate that activation of the

glucocorticoid hormone system reduces the lifespan of Mecp2-/y mice and the symptom-free lifetime of

Mecp2+/- mice and that treatment with the GR inhibitor RU486 has an opposite effect as it prolongs the

lifetime until symptom onset for Mecp2+/- mice and improves motor functions of Mecp2-null male mice. Our

findings provide evidence for the contribution of the glucocorticoid hormone system to RTT motor symptoms

and suggests this system as a potential therapeutic target for RTT. In paper two and three, we focused on the

molecular events that lead to the development of primary malignant brain tumors. In paper two, we performed

a series of transplantation experiments with genetically perturbed cells. We could show that the individual

over-expression of potent oncogenes in neural stem/progenitor cells of the same cell pool leads to distinct

tumor types. Furthermore, we demonstrated that it is possible to convert one tumor type into another one and

that this is determined by the order of genetic events. In a second part of this study we could show a hitherto

unknown aspect of AT/RT and rhabdoid tumor biology, an activation of the UPR. We provide experimental

evidence that AT/RT and rhabdoid tumor cells with reduced or absent SMARCB1 levels are sensitive toward a

further increase in ER stress. In paper three, we studied the PcG protein BMI1 and its effect on neural

stem/progenitor cells and tumor formation. We observed a strong promotion of self-renewal, expansion and

survival in adult neural stem/progenitor cells upon over-expression of Bmi1 in vitro but found it incapable of

transforming cells as no tumors developed in intracranial transplantation experiments with Bmi1

over-expressing wild-type cells or Trp53-/- cells. Thus, we assume BMI1 to promote stem cell properties and to

act as a facilitator of transforming events induced by other oncogenes. Furthermore, we could identify four

novel direct BMI1 target genes whose molecular function may contribute to the known BMI1 effects, thus

expanding the BMI1 network. Taken together, the findings presented in this thesis emphasize the key role of

master regulators in the pathology of brain diseases and for the development of causal therapies. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • PhD Hermanson, Ola, Department of Neuroscience Karolinska Institutet Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Rett syndrome, brain tumor development, gene regulation, neural stem cells, cell of origin, BMI1
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:64
pages
105 pages
defense location
Segerfalksalen, Wallenberg Neuroscience Center, Lund, Sweden
defense date
2012-09-21 14:30
ISSN
1652-8220
ISBN
978-91-87189-27-2
language
English
LU publication?
yes
id
c6ef1f10-8c71-4c3a-bbae-30b4d832e940 (old id 3044840)
date added to LUP
2012-08-29 08:37:09
date last changed
2016-09-19 08:45:00
@misc{c6ef1f10-8c71-4c3a-bbae-30b4d832e940,
  abstract     = {In paper one, we investigated how the pharmacological activation and inhibition of the glucocorticoid system<br/><br>
affects lifespan and symptoms in a mouse model for RTT. We performed a long-term drug treatment study with<br/><br>
the GR activator corticosterone and the GR inhibitor RU486 under which we measured the lifespan and onset<br/><br>
of RTT-like symptoms of male Mecp2-null and female Mecp2 heterozygous mice in comparison to untreated<br/><br>
mutant and to treated and untreated wild-type animals. We could demonstrate that activation of the<br/><br>
glucocorticoid hormone system reduces the lifespan of Mecp2-/y mice and the symptom-free lifetime of<br/><br>
Mecp2+/- mice and that treatment with the GR inhibitor RU486 has an opposite effect as it prolongs the<br/><br>
lifetime until symptom onset for Mecp2+/- mice and improves motor functions of Mecp2-null male mice. Our<br/><br>
findings provide evidence for the contribution of the glucocorticoid hormone system to RTT motor symptoms<br/><br>
and suggests this system as a potential therapeutic target for RTT. In paper two and three, we focused on the<br/><br>
molecular events that lead to the development of primary malignant brain tumors. In paper two, we performed<br/><br>
a series of transplantation experiments with genetically perturbed cells. We could show that the individual<br/><br>
over-expression of potent oncogenes in neural stem/progenitor cells of the same cell pool leads to distinct<br/><br>
tumor types. Furthermore, we demonstrated that it is possible to convert one tumor type into another one and<br/><br>
that this is determined by the order of genetic events. In a second part of this study we could show a hitherto<br/><br>
unknown aspect of AT/RT and rhabdoid tumor biology, an activation of the UPR. We provide experimental<br/><br>
evidence that AT/RT and rhabdoid tumor cells with reduced or absent SMARCB1 levels are sensitive toward a<br/><br>
further increase in ER stress. In paper three, we studied the PcG protein BMI1 and its effect on neural<br/><br>
stem/progenitor cells and tumor formation. We observed a strong promotion of self-renewal, expansion and<br/><br>
survival in adult neural stem/progenitor cells upon over-expression of Bmi1 in vitro but found it incapable of<br/><br>
transforming cells as no tumors developed in intracranial transplantation experiments with Bmi1<br/><br>
over-expressing wild-type cells or Trp53-/- cells. Thus, we assume BMI1 to promote stem cell properties and to<br/><br>
act as a facilitator of transforming events induced by other oncogenes. Furthermore, we could identify four<br/><br>
novel direct BMI1 target genes whose molecular function may contribute to the known BMI1 effects, thus<br/><br>
expanding the BMI1 network. Taken together, the findings presented in this thesis emphasize the key role of<br/><br>
master regulators in the pathology of brain diseases and for the development of causal therapies.},
  author       = {Braun, Sebastian},
  isbn         = {978-91-87189-27-2},
  issn         = {1652-8220},
  keyword      = {Rett syndrome,brain tumor development,gene regulation,neural stem cells,cell of origin,BMI1},
  language     = {eng},
  pages        = {105},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Downstream effects of master regulators in two brain diseases.},
  volume       = {2012:64},
  year         = {2012},
}