| dc.description.abstracteng | The nuclear lamina is a protein meshwork at the inner side of the inner nuclear membrane
and connects to essential cellular structures like chromatin, the nuclear pore complex and the
cytoskeleton. The nuclear lamina is comprised of A-type lamins (lamin A, C and C2), B-type
lamins (lamin B1, B2 and B3) and lamina associated proteins. Progerin is a altered form of
Lamin A, which causes severe ageing-like effects of the Hutchinson-Gilford progeria syndrome.
Progerin was also found in cells of normal aged individuals. Therefore, it is conceivable that the
expression of Progerin is linked to the process of ageing and its effects. How the cellular effects
of Progerin expression, like misfolded nuclei, decreased heterochromatin, increased apoptosis
and increased DNA damage are mediated from the cellular to the organismic level is not well
understood. It is conceivable however that stem cells play an important role in this process,
since the early loss of hair is a typical symptom of HGPS and in HGPS-mouse-models a decrease
of hair-follicle stem cell proliferation was reported. Also the loss of subcutaneous fat and reduced
wound healing, found in HGPS patients and elderly people, indicates impairment of stem cell
function. In Drosophila expression of the lamina proteins lamin Dm0 and Kugelkern induces
effects similar to those observed in HGPS patients and HGPS-animal-models. In the course of
this work, lamin Dm0 and Kugelkern were found to drastically reduce stem cell proliferation
in the Drosophila midgut. Since the midgut is a relatively simple organ, with only 5 cell types
and low degree of infoldings, it offers many benefits as a system to study stem cell behavior;
and in this context, the effect of lamin Dm0 and Kugelkern on intestinal stem cells.
In this work the mechanism in which lamin Dm0 and Kugelkern act on intestinal stem cells
was investigated. It is shown, that lamin Dm0 Kugelkern overexpression does not permanently
damage intestinal stem cells or impair their function irreversibly. That the effects of lamin
Dm0 and Kugelkern overexpression are likely not due to impaired nuclear transport. And that
the inhibiting effect of lamin Dm0 on ISC proliferation is pinpointed to the impairment of the
JAK/STAT signaling pathway on a transcriptional level. | de |