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Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity

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Abstract

Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ 2 = 19.1, df = 2, p = 7.0 × 10−5). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by area under the curve, AUC 0–30 and AUC 30–120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggests a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological functionthat is critical to survivability and reproductive success.

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Acknowledgments

This works was supported in part by Grants 5R01 MH081203-05, 3R01 MH08120302S1, 5R21-R33 MH089917-03 to JMS, and by a Graduate Student Fellowship from the Coleman Institute for Cognitive Disabilities. This work was also supported by the the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), funds from the German Federal Ministry of Education and Research (German Center for Vertigo and Balance Disorders, Grant 01 EO 0901; Infrafrontier, Grant 01KX1012), and the German Center for Diabetes Research (DZD).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics and Human Medical Genetics and Neuroscience Programs, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA

    J. G. Keeney, M. S. O’Bleness, N. Anderson, J. M. Davis & J. M. Sikela

  2. Department of Cell and Developmental Biology and Neuroscience Programs, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA

    N. Arevalo, N. Busquet, W. Chick & D. Restrepo

  3. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany

    J. Rozman, S. M. Hölter, L. Garrett, M. Horsch, J. Beckers & M. Hrabě de Angelis

  4. German Center for Diabetes Research (DZD), Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany

    J. Rozman, J. Beckers & M. Hrabě de Angelis

  5. Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354, Freising-Weihenstephan, Germany

    J. Beckers & M. Hrabě de Angelis

  6. German Center for Vertigo and Balance Disorders, Munich, Germany

    W. Wurst

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

    S. M. Hölter, L. Garrett & W. Wurst

  8. Chair of Developmental Genetics, Technische Universität München-Weihenstephan, c/o Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany

    W. Wurst

  9. Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Standort München, Schillerstrasse 44, 80336, Munich, Germany

    W. Wurst

  10. Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstrasse 44, 80336, Munich, Germany

    W. Wurst

  11. Chair for Molecular Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius Center for Nutritional Medicine, D-85350, Freising, Germany

    M. Klingenspor

  12. ZIEL – Center for Nutrition and Food Sciences, Technische Universität München, D-85350, Freising, Germany

    M. Klingenspor

Authors
  1. J. G. Keeney
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  2. M. S. O’Bleness
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  3. N. Anderson
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  4. J. M. Davis
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  5. N. Arevalo
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  6. N. Busquet
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  7. W. Chick
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  8. J. Rozman
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  9. S. M. Hölter
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  10. L. Garrett
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  11. M. Horsch
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  12. J. Beckers
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  13. W. Wurst
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  14. M. Klingenspor
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  15. D. Restrepo
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  16. M. Hrabě de Angelis
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  17. J. M. Sikela
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Consortia

German Mouse Clinic Consortium

Corresponding authors

Correspondence to M. Hrabě de Angelis or J. M. Sikela.

Additional information

German Mouse Clinic Consortium: The members of the German Mouse Clinic Consortium are listed in the Appendix.

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Appendix

Appendix

German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany

  • Thure Adler 1,2

  • Antonio Aguilar-Pimentel1,3

  • Oana Amarie1,4

  • Lore Becker 1,5

  • Johannes Beckers1,18,19

  • Raffi Bekeredjian6

  • Dirk H. Busch 2

  • Oliver Eickelberg 4

  • Lillian Garrett1,8

  • Jochen Graw 8

  • Wolfgang Hans1

  • Sabine M. Hölter 1,8

  • Marion Horsch1

  • Dirk Janik1,7

  • Martin Klingenspor9,10

  • Thomas Klopstock 5,16,20,21

  • Kristin Moreth1

  • Frauke Neff1,7

  • Markus Ollert3,11

  • Oliver Puk1,8

  • Ildikó Rácz1,12

  • Birgit Rathkolb 1,13,19

  • Jan Rozman 1,19

  • Tobias Stöger1,4

  • Eckhard Wolf 13

  • Wolfgang Wurst 8,14,15,16,17,21

  • Ali Önder Yildrim4

  • Andreas Zimmer12

  • Martin Hrabě de Angelis 1,18,19

  • Valérie Gailus-Durner 1

  • Helmut Fuchs 1

  1. 1.

    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany

  2. 2.

    Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 9, 81675 Munich, Germany

  3. 3.

    Department of Dermatology and Allergy, Biederstein, Klinikum rechts der Isar, Technische Universität München (TUM), Biedersteiner Str. 29, 80802 Munich,

  4. 4.

    Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany and Member of the German Center for Lung Research

  5. 5.

    Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Ziemssenstrasse 1a, 80336 Munich, Germany

  6. 6.

    Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

  7. 7.

    Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany

  8. 8.

    Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany

  9. 9.

    Chair for Molecular Nutritional Medicine, Technische Universität München, Else Kröner-Fresenius Center for Nutritional Medicine, 85350 Freising, Germany

  10. 10.

    ZIEL – Center for Nutrition and Food Sciences, Technische Universität München, 85350 Freising, Germany

  11. 11.

    Clinical Research Group Molecular Allergology, Center of Allergy and Environment Munich (ZAUM), Technische Universität München (TUM), and Institute for Allergy Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

  12. 12.

    Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany

  13. 13.

    Ludwig-Maximilians-Universität München, Gene Center, Institute of Molecular Animal Breeding and Biotechnology, Feodor-Lynen Strasse 25, 81377 Munich, Germany

  14. 14.

    Chair of Developmental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany

  15. 15.

    Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany

  16. 16.

    Deutsches Institut für Neurodegenerative Erkrankungen (DZNE) Site Munich, Schillerstrasse 44, 80336 Munich, Germany

  17. 17.

    Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstrasse 44, 80336 Munich, Germany

  18. 18.

    Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany

  19. 19.

    Member of German Center for Diabetes Research (DZD), Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany

  20. 20.

    German Network for Mitochondrial Disorders (mitoNET)

  21. 21.

    German Center for Vertigo and Balance Disorders, Munich, Germany

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Keeney, J.G., O’Bleness, M.S., Anderson, N. et al. Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity. Mamm Genome 26, 33–42 (2015). https://doi.org/10.1007/s00335-014-9545-8

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