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@ARTICLE{Bronckers:136944,
      author       = {Bronckers, Antonius L J J and Gueneli, Nur and
                      Lüllmann-Rauch, Renate and Schneppenheim, Janna and Moraru,
                      Andreea P and Himmerkus, Nina and Bervoets, Theodore J and
                      Fluhrer, Regina and Everts, Vincent and Saftig, Paul and
                      Schröder, Bernd},
      title        = {{T}he intramembrane protease {SPPL}2{A} is critical for
                      tooth enamel formation.},
      journal      = {Journal of bone and mineral research},
      volume       = {28},
      number       = {7},
      issn         = {0884-0431},
      address      = {Hoboken, NJ [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2020-03266},
      pages        = {1622-1630},
      year         = {2013},
      abstract     = {Intramembrane proteases are critically involved in signal
                      transduction and membrane protein turnover.
                      Signal-peptide-peptidase-like 2a (SPPL2A), a
                      presenilin-homologue residing in lysosomes/late endosomes,
                      cleaves type II-oriented transmembrane proteins. We recently
                      identified SPPL2A as the enzyme controlling turnover and
                      functions of the invariant chain (CD74) of the major
                      histocompatibility complex II (MHCII) and demonstrated
                      critical importance of this process for B cell development.
                      Surprisingly, we found that SPPL2A is critical for formation
                      of dental enamel. In Sppl2a knockout mice, enamel of the
                      erupted incisors was chalky white and rapidly eroded after
                      eruption. SPPL2A was found to be expressed in enamel
                      epithelium during secretory and maturation stage
                      amelogenesis. Mineral content of enamel in Sppl2a⁻/⁻
                      incisors was inhomogeneous and reduced by $∼20\%$ compared
                      to wild-type mice with the most pronounced reduction at the
                      mesial side. Frequently, disruption of the enamel layer and
                      localized detachment of the most superficial enamel layer
                      was observed in the knockout incisors leading to an uneven
                      enamel surface. In Sppl2a null mice, morphology and function
                      of secretory stage ameloblasts were not noticeably different
                      from that of wild-type mice. However, maturation stage
                      ameloblasts showed reduced height and a characteristic
                      undulation of the ameloblast layer with localized adherence
                      of the cells to the outer enamel. This was reflected in a
                      delayed and incomplete resorption of the proteinaceous
                      enamel matrix. Thus, we conclude that intramembrane
                      proteolysis by SPPL2A is essential for maintaining cellular
                      homeostasis of ameloblasts. Because modulation of SPPL2A
                      activity appears to be an attractive therapeutic target to
                      deplete B cells and treat autoimmunity, interference with
                      tooth enamel formation should be investigated as a possible
                      adverse effect of pharmacological SPPL2A inhibitors in
                      humans.},
      keywords     = {Ameloblasts: enzymology / Animals / Antigens,
                      Differentiation, B-Lymphocyte: genetics / Antigens,
                      Differentiation, B-Lymphocyte: metabolism / Aspartic Acid
                      Endopeptidases: genetics / Aspartic Acid Endopeptidases:
                      metabolism / Dental Enamel: enzymology / Dental Enamel:
                      growth $\&$ development / Histocompatibility Antigens Class
                      II: genetics / Histocompatibility Antigens Class II:
                      metabolism / Incisor: enzymology / Incisor: growth $\&$
                      development / Membrane Proteins: genetics / Membrane
                      Proteins: metabolism / Mice / Mice, Knockout / Proteolysis /
                      Antigens, Differentiation, B-Lymphocyte (NLM Chemicals) /
                      Histocompatibility Antigens Class II (NLM Chemicals) /
                      Membrane Proteins (NLM Chemicals) / invariant chain (NLM
                      Chemicals) / Aspartic Acid Endopeptidases (NLM Chemicals) /
                      SPPL2a protein, mouse (NLM Chemicals)},
      cin          = {AG Fluhrer},
      ddc          = {610},
      cid          = {I:(DE-2719)1110000-2},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:23426979},
      doi          = {10.1002/jbmr.1895},
      url          = {https://pub.dzne.de/record/136944},
}