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Cited by 17Ocular Disorders and TreatmentsProtein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase Signaling

Impaired development of the Harderian gland in mutant protein phosphatase 2A transgenic mice

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Schild, Andreas, Isenmann, Stefan, Tanimoto, Naoyuki, Tonagel, Felix, Seeliger, Mathias W., Ittner, Lars M., Kretz, Alexandra, Ogris, Egon +1 more·2006·Mechanisms of Development
DOI 10.1016/j.mod.2006.03.003
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Abstract

Although Harderian glands are especially large in rodents, many features of this retroocular gland, including its development and function, are not well established. Protein phosphatase 2A (PP2A) is a family of heterotrimeric enzymes expressed in this gland. PP2A substrate specificity is determined by regulatory subunits with leucine 309 of the catalytic subunit playing a crucial role in the recruitment of regulatory subunits into the complex in vitro. Here we expressed an L309A mutant catalytic subunit in Harderian gland of transgenic mice. We found a delayed postnatal development and hypoplasia of the gland, causing enophthalmos. To determine why expression of the L309A mutant caused this phenotype, we determined the PP2A subunit composition. We found an altered subunit composition in the transgenic gland that was accompanied by pronounced changes of proteins regulating cell adhesion. Specifically, cadherin and beta-catenin were dramatically reduced and shifted to the cytosol. Furthermore, we found an inactivating phosphorylation of the cadherin-directed glycogen synthase kinase-3beta. In conclusion, the carboxy-terminal leucine L309 of the PP2A catalytic subunit determines PP2A heterotrimer composition in vivo. Moreover, our data demonstrate that PP2A subunit composition plays a crucial role in regulating cell adhesion and as a consequence in the development of the Harderian gland.

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  • The Harderian gland in L309A Cα transgenic mice shows reduced E-cadherin and β-catenin levels and a spatial shift of their expression from the membrane to the cytosol.

    “the Harderian gland showed reduced E-cadherin and β-catenin levels and their expression was spatially shifted from the membrane to the cytosol.”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [91]

  • Moderate transgenic expression of the dominant-negative L309A Cα mutant in the Harderian gland causes delayed development and hypoplasia of this gland, accompanied by enophthalmos in a significant number of mice.

    “Moderate transgenic expression of the dominant negative L309A Cα mutant in the Harderian gland caused a delayed development and hypoplasia of this gland, accompanied by a slit-eye phenotype (enophthalmos) in a significant number of mice [91].”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [91]

  • L309A Cα transgenic mice show increased GSK-3β phosphorylation at Ser9.

    “In addition, an increase in GSK-3β phosphorylation (Ser9) was observed [91].”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [91]

  • Retinal function remains unaffected in mice expressing the L309A Cα mutant in the Harderian gland.

    “Retinal function in the transgenic animals remained unaffected [91].”

    From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [91]

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Authors
Schild, A., Isenmann, S., Tanimoto, N., Tonagel, F., Seeliger, M. W., Ittner, L. M., Kretz, A., Ogris, E., & Götz, J.
Affiliations
  • University of Zurich (CH)
  • Jena University Hospital (DE)
  • University of Tübingen (DE)
  • The University of Sydney (AU)
  • Max Perutz Labs (AT)
ORCID
Venue
Mechanisms of Development
Publisher
Elsevier BV
Published
2006-05
Volume
123
Issue
5
Pages
362-371
ISSN
0925-4773 (ISSN-L)
DOI
10.1016/j.mod.2006.03.003
OpenAlex
W2093113783
Cited by
17
References
59
Citations by year
2024: 1 · 2018: 1 · 2016: 1 · 2013: 1
FWCI
1.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Mechanisms of Development (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
EMDO Stiftung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Ocular Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Harderian gland, protein phosphatase 2A, PP2A catalytic subunit, transgenic mice, gland development, enophthalmos, cadherins, β-catenin, cell adhesion, glycogen synthase kinase-3β, postnatal development
MeSH terms
Animals, Animals, Newborn, Cell Adhesion, Eye Abnormalities, Gene Expression Regulation, Harderian Gland, Leucine, Mice, Transgenic, Mutation, Phosphoprotein Phosphatases, Dimerization, Catalytic Domain, Protein Subunits, Mice, Protein Phosphatase 2

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