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| Home > Publications database > ELP1’s Role in Cerebellar Development: Implications for Familial Dysautonomia and SHH-Medulloblastoma > print |
| Home > Publications database > ELP1’s Role in Cerebellar Development: Implications for Familial Dysautonomia and SHH-Medulloblastoma > print |
| 001 | 294894 | ||
| 005 | 20241213140945.0 | ||
| 024 | 7 | _ | |a 10.11588/HEIDOK.00035455 |2 doi |
| 037 | _ | _ | |a DKFZ-2024-02604 |
| 100 | 1 | _ | |a Arnskötter, Carl Frederik |0 P:(DE-HGF)0 |b 0 |g male |
| 245 | _ | _ | |a ELP1’s Role in Cerebellar Development: Implications for Familial Dysautonomia and SHH-Medulloblastoma |
| 260 | _ | _ | |c 2024 |b Heidelberg University Library |
| 336 | 7 | _ | |a Output Types/Dissertation |2 DataCite |
| 336 | 7 | _ | |a DISSERTATION |2 ORCID |
| 336 | 7 | _ | |a PHDTHESIS |2 BibTeX |
| 336 | 7 | _ | |a Thesis |0 2 |2 EndNote |
| 336 | 7 | _ | |a Dissertation / PhD Thesis |b phd |m phd |0 PUB:(DE-HGF)11 |s 1734095364_30944 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a doctoralThesis |2 DRIVER |
| 500 | _ | _ | |a Oral examination: September 30th, 2024 / doctoral degree |
| 502 | _ | _ | |a Dissertation, Universität Heidelberg, 2024 |c Universität Heidelberg |b Dissertation |
| 520 | _ | _ | |a The cerebellum plays a pivotal role in the coordination of motor movement, behavior, and language. Abnormalities in cerebellar development can have two opposing, catastrophic effects. On the one hand, they can cause neuronal degeneration, which may manifest as cerebellar ataxias and other neurological disorders. On the other hand, they can also result in the excessive proliferation of progenitor cell types, which subsequently lead to the formation of tumors. In my doctoral dissertation, I investigated the role of the Elongator complex protein ELP1 in the context of cerebellar development. A reduction or loss of ELP1 protein in neurons has been linked to the neurodegenerative disease Familial Dysautonomia. In contrast, heterozygous germline loss-of-function mutations predispose young children to the formation of SHH-medulloblastoma, a tumor subtype in the cerebellum caused by the excessive proliferation of granule cell progenitors (GCP). In my first project, I examined the impact of a GCP-specific Elp1 knockout in mice, which resulted in a reduction in cerebellum size and the onset of ataxia, mimicking the impaired gait observed in Familial Dysautonomia patients. My findings indicated that this phenotype was attributable to GCP cell death at earlier stages, resulting in a reduction in the granule cell pool and synaptic complexity at subsequent stages. In my second project, I adapted existing protocols and established humanized induced pluripotent stem cell (iPSC)-derived models for the GCP lineage and cerebellar development, thereby overcoming species-specific boundaries. I demonstrated that the in vitro models reflect the characteristics of cerebellar cell types. In my third project, I employed these humanized models to examine the mechanism by which heterozygous germline mutations in ELP1 (ELP1HET) predispose GCPs to malignant transformation. I generated patient-specific ELP1HET iPSC lines and demonstrated that they exhibit a distorted DNA damage response. Ultimately, I differentiated these ELP1HET iPSCs into the novel established cerebellar models and investigated the impact of ELP1HET on the specific context of cerebellar development and cell types. In conclusion, the results of my doctoral dissertation may contribute to the understanding of the disease etiology and potential treatments for patients affected by either neurodegenerative disease Familial Dysautonomia or SHH-medulloblastoma. |
| 536 | _ | _ | |a 312 - Funktionelle und strukturelle Genomforschung (POF4-312) |0 G:(DE-HGF)POF4-312 |c POF4-312 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to DataCite |
| 650 | _ | 7 | |a 500 Natural sciences and mathematics |2 Other |
| 650 | _ | 7 | |a 570 Life sciences |2 Other |
| 773 | _ | _ | |a 10.11588/HEIDOK.00035455 |
| 909 | C | O | |p VDB |o oai:inrepo02.dkfz.de:294894 |
| 910 | 1 | _ | |a Deutsches Krebsforschungszentrum |0 I:(DE-588b)2036810-0 |k DKFZ |b 0 |6 P:(DE-HGF)0 |
| 913 | 1 | _ | |a DE-HGF |b Gesundheit |l Krebsforschung |1 G:(DE-HGF)POF4-310 |0 G:(DE-HGF)POF4-312 |3 G:(DE-HGF)POF4 |2 G:(DE-HGF)POF4-300 |4 G:(DE-HGF)POF |v Funktionelle und strukturelle Genomforschung |x 0 |
| 914 | 1 | _ | |y 2024 |
| 920 | 1 | _ | |0 I:(DE-He78)B062-20160331 |k B062 |l B062 Pädiatrische Neuroonkologie |x 0 |
| 920 | 1 | _ | |0 I:(DE-He78)B430-20160331 |k B430 |l Entwicklungsbiolog. Ursprünge pädiatrischer Krebserkrankungen |x 1 |
| 980 | _ | _ | |a phd |
| 980 | _ | _ | |a VDB |
| 980 | _ | _ | |a I:(DE-He78)B062-20160331 |
| 980 | _ | _ | |a I:(DE-He78)B430-20160331 |
| 980 | _ | _ | |a UNRESTRICTED |
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