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@PHDTHESIS{Arnsktter:294894,
      author       = {Arnskötter, Carl Frederik$^*$},
      title        = {{ELP}1’s {R}ole in {C}erebellar {D}evelopment:
                      {I}mplications for {F}amilial {D}ysautonomia and
                      {SHH}-{M}edulloblastoma},
      school       = {Universität Heidelberg},
      type         = {Dissertation},
      publisher    = {Heidelberg University Library},
      reportid     = {DKFZ-2024-02604},
      year         = {2024},
      note         = {Oral examination: September 30th, 2024 / doctoral degree;
                      Dissertation, Universität Heidelberg, 2024},
      abstract     = {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.},
      keywords     = {500 Natural sciences and mathematics (Other) / 570 Life
                      sciences (Other)},
      cin          = {B062 / B430},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)B430-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.11588/HEIDOK.00035455},
      url          = {https://inrepo02.dkfz.de/record/294894},
}