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@ARTICLE{Hellwig:143312,
      author       = {M. Hellwig and M. C. Lauffer and M. Bockmayr and M. Spohn
                      and D. J. Merk and L. Harrison and J. Ahlfeld and A.
                      Kitowski and J. E. Neumann and J. Ohli and D. Holdhof and J.
                      Niesen and M. Schoof and M. Kool$^*$ and C. Kraus and C.
                      Zweier and D. Holmberg and U. Schüller},
      title        = {{TCF}4 ({E}2-2) harbors tumor suppressive functions in
                      {SHH} medulloblastoma.},
      journal      = {Acta neuropathologica},
      volume       = {137},
      number       = {4},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2019-00902},
      pages        = {657 - 673},
      year         = {2019},
      abstract     = {The TCF4 gene encodes for the basic helix-loop-helix
                      transcription factor 4 (TCF4), which plays an important role
                      in the development of the central nervous system (CNS).
                      Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins
                      syndrome (PTHS), a severe neurodevelopmental disorder.
                      Recently, the screening of a large cohort of medulloblastoma
                      (MB), a highly aggressive embryonal brain tumor, revealed
                      almost $20\%$ of adult patients with MB of the Sonic
                      hedgehog (SHH) subtype carrying somatic TCF4 mutations.
                      Interestingly, many of these mutations have previously been
                      detected as germline mutations in patients with PTHS. We
                      show here that overexpression of wild-type TCF4 in vitro
                      significantly suppresses cell proliferation in MB cells,
                      whereas mutant TCF4 proteins do not to the same extent.
                      Furthermore, RNA sequencing revealed significant
                      upregulation of multiple well-known tumor suppressors upon
                      expression of wild-type TCF4. In vivo, a prenatal knockout
                      of Tcf4 in mice caused a significant increase in apoptosis
                      accompanied by a decreased proliferation and failed
                      migration of cerebellar granule neuron precursor cells
                      (CGNP), which are thought to be the cells of origin for SHH
                      MB. In contrast, postnatal in vitro and in vivo knockouts of
                      Tcf4 with and without an additional constitutive activation
                      of the SHH pathway led to significantly increased
                      proliferation of CGNP or MB cells. Finally, publicly
                      available data from human MB show that relatively low
                      expression levels of TCF4 significantly correlate with a
                      worse clinical outcome. These results not only point to
                      time-specific roles of Tcf4 during cerebellar development
                      but also suggest a functional linkage between TCF4 mutations
                      and the formation of SHH MB, proposing that TCF4 acts as a
                      tumor suppressor during postnatal stages of cerebellar
                      development.},
      cin          = {B062 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30830316},
      doi          = {10.1007/s00401-019-01982-5},
      url          = {https://inrepo02.dkfz.de/record/143312},
}