| dc.contributor.advisor | Emmert, Steffen Prof. Dr. | |
| dc.contributor.author | Seebode, Christina | |
| dc.date.accessioned | 2015-12-11T11:11:59Z | |
| dc.date.available | 2015-12-11T11:11:59Z | |
| dc.date.issued | 2015-12-11 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0028-8670-D | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5339 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | The role of SNAP29 during epidermal differentiation | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Schön, Michael P. Prof. Dr. | |
| dc.date.examination | 2015-10-02 | |
| dc.description.abstracteng | The human CEDNIK syndrome is caused by loss-of-function mutations in the SNAP29 gene, encoding a member of the SNARE family of proteins. So far, no Snap29-deficient mammalian animal models have been described for this rare neurocutaneous syndrome and this work reports the generation and characterization of a total (Snap29-/-) as well as keratinocyte specific (Snap29fl/fl/K14-Cre) Snap29 knockout mouse line. Both Snap29-deficient mouse models developed an ichthyotic phenotype closely resembling the human epidermal CEDNIK syndrome phenotype. Thus, both lines can be used as beneficial models to further enlighten the unique impact of SNAP29 in epidermal differentiation as well as in understanding the pathophysiological mechanisms in common epidermal differentiation disorders and they provide a deeper insight into the molecular basis of the pathogenesis of CEDNIK syndrome.
Using immunohistochemistry, SNAP29 deficiency was found to result in acanthosis and hyperkeratosis as well as in abnormal keratinocyte differentiation with increased proliferation in both mutant mouse lines. In addition, Snap29-deficient mice revealed a severely impaired cutaneous permeability barrier function accompanied by neonatal lethality. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Furthermore, ultrastructural analyses revealed malformed LBs and markedly decreased deposition of LB contents in mutant mice epidermis indicating a severe impairment in LB function in the epidermis due to the Snap29 knockout. Thus, SNAP29 is essential for LB maturation and secretion as demonstrated by abnormal lipid profiles, and an impaired barrier formation, which are most likely due to an impaired vesicular trafficking.
In addition to the impact on terminal keratinocyte differentiation, ablation of SNAP29 affects ER stress and autophagy. By western blot analyses, SNAP29 ablation was found to result in a strong induction of the ER stress marker CHOP (C/EBP homologous protein) in mutant mice and the autophagosomal marker LC3B-II was increased under starvation and bafilomycin A1 treatment, whereas p62/SQSTM1 protein amounts remained unchanged.
In conclusion, this work contributes to the substantial role of SNAP29 in epidermal differentiation, particularly in LB formation and maturation. SNAP29 is also involved in the complex machinery of autophagy. | de |
| dc.contributor.coReferee | Hahn, Heidi Prof. Dr. | |
| dc.contributor.thirdReferee | Brockmöller, Jürgen Prof. Dr. | |
| dc.subject.eng | epidermal differentiation | de |
| dc.subject.eng | mouse model | de |
| dc.subject.eng | ichthyosis | de |
| dc.subject.eng | CEDNIK | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0028-8670-D-7 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Medizin (PPN619874732) | de |
| dc.subject.gokfull | Dermatologie / Venerologie - Allgemein- und Gesamtdarstellungen (PPN619876174) | de |
| dc.identifier.ppn | 843851872 | |