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Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 416insG mice

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Abstract

A new spontaneous mouse mutant was characterized by closed eyelids at weaning and without apparent eyes (provisional gene name, eyeless; provisional gene symbol, eyl). The mutation follows a recessive pattern of inheritance and was mapped to the region of chromosome 19 containing Pitx3. Genetic complementation tests using Pitx3 ak/+ mice confirmed eyl as a new allele of Pitx3 (Pitx3 eyl). Sequencing of the Pitx3 gene in eyl mutants identified an inserted G after cDNA position 416 (416insG; exon 4). The shifted open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but followed by 121 new amino acids. The novel Pitx3 eyl/eyl mutants expressed ophthalmological and brain defects similar to Pitx3 ak/ak mice: microphthalmia or anophthalmia and loss of dopamine neurons of the substantia nigra. In addition, we observed in the homozygous eyeless mutants increased extramedullary hematopoiesis in the spleen, frequently liver steatosis, and reduced body weight. There were also several behavioral changes in the homozygous mutants, including reduced forelimb grip strength and increased nociception. In addition to these alterations in both sexes, we observed in female Pitx3 eyl/eyl mice increased anxiety-related behavior, reduced locomotor activity, reduced object exploration, and increased social contacts; however, we observed decreased anxiety-related behavior and increased arousal in males. Most of these defects identified in the new Pitx3 mutation are observed in Parkinson patients, making the Pitx3 eyl mutant a valuable new model. It is the first mouse mutant carrying a point mutation within the coding region of Pitx3.

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Acknowledgments

This work was supported at least in part by the German National Genome Research Network (NGFN; grants 01GS0850, 01GS0851, 01GS0852, 01GS0854, 01GS0869, 01GS0853, 01GS08156, 01GR0430, 01GR0434, 01GR0438, 01KW9948, and R0313435B), the Deutsche Forschungsgemeinschaft (FOR926), and the European Union (FP6, EUMODIC, LSHG-CT-2006-037188). The expert technical assistance of Miriam Backs, Erika Bürkle, Christine Führmann, Anita Hellemons, Elfi Holupirek, Regina Kneuttinger, Maria Kugler, Astrid Markert, Jacqueline Müller, Eleonore Samson, Bahar Sanli-Bonazzi, Sandra Schädler, Florian Schleicher, Daniela Schmid, Ann-Elisabeth Schwarz, Reinhard Seeliger, Monika Stadler, Susanne Wittich, and Claudia Zeller is gratefully acknowledged.

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Author notes

  1. Claudia Dalke

    Present address: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

  2. Svetoslav Kalaydjiev

    Present address: Miltenyi Biotec Ltd., Bisley, UK

  3. Ines Bolle & Leticia Quintanilla-Martinez

    Present address: Institute of Pathology, University Hospital Tübingen, Tubingen, Germany

Authors and Affiliations

  1. Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    Michael Rosemann & Michael Atkinson

  2. Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    Alesia Ivashkevich, Julia Calzada-Wack, Sandra Kunder, Leticia Quintanilla-Martinez, Irene Esposito & Ulrich Heinzmann

  3. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    Jack Favor

  4. Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany

    Claudia Dalke, Sabine M. Hölter & Jochen Graw

  5. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    Wolfgang Hans, Marion Horsch, Jan Rozman, Beatrix Naton, Valerie Gailus-Durner, Helmut Fuchs, Johannes Beckers, Wolfgang Wurst & Martin Hrabé de Angelis

  6. Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    Ines Bolle & Holger Schulz

  7. Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Munich, Germany

    Lore Becker & Thomas Klopstock

  8. Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, Munich, Germany

    Martina Klempt, Birgit Rathkolb & Eckhard Wolf

  9. Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany

    Ildikó Rácz & Andreas Zimmer

  10. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany

    Svetoslav Kalaydjiev, Thure Adler & Dirk H. Busch

  11. Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands

    J. Peter H. Burbach & Marten P. Smidt

  12. Nutrition and Food Research Center, Technische Universität München, Freising, Germany

    Jan Rozman & Martin Klingenspor

  13. Clinical Research Division of Molecular and Clinical Allergotoxicology, Department of Dermatology and Allergy, Technische Universität München, Munich, Germany

    Antonio Aguilar & Markus Ollert

  14. Experimental Genetics, Technical University Munich, Freising-Weihenstephan, Germany

    Johannes Beckers

  15. Institute of Pathology, Technische Universität München, Munich, Germany

    Irene Esposito & Martin Hrabé de Angelis

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  1. Michael Rosemann
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Corresponding author

Correspondence to Jochen Graw.

Additional information

M. Rosemann and A. Ivashkevich contributed equally to this work.

A broad phenotypical analysis of wild-type controls and eyl3 -/- mice was done at the German Mouse Clinic. The complete set of data will be published at www.europhenome.org. The expression data obtained from livers of eyl mutant mice have been submitted to the GEO database (GSE15336), including a full description of our microarray platform (GPL3697).

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Rosemann, M., Ivashkevich, A., Favor, J. et al. Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 416insG mice. Mamm Genome 21, 13–27 (2010). https://doi.org/10.1007/s00335-009-9235-0

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