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A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects

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ABSTRACT

Mammals have three HP1 protein isotypes HP1β (CBX1), HP1γ (CBX3) and HP1α (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3 hypo) causes a severe postnatal mortality with around 99% of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3 hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3 hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3 hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3 hypo/hypo pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for non-shivering themogenesis. We suggest that it is the small size of the Cbx3 hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality.

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Acknowledgements

We are grateful to Drs Nadine Binart, Miguel Constância and Mike Soares for critically reading the manuscript, and to Drs Irene and Kenneth Söderhäll for their help and support. This work was supported by the University of Uppsala, Department for Organismic Biology, and by the VR grant 621-2009-5715 from the Swedish Research Council to Kenneth Söderhäll.

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Authors and Affiliations

  1. Sub-department of Evolution & Development, Center for Evolutionary Biology, Uppsala University, Norbyvägen 18A, S-75236, Uppsala, Sweden

    Ebru Aydin, Lijuan Hu & Reinald Fundele

  2. Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), Albinusdreef 2, 2300 RC, Leiden, The Netherlands

    Dick-Paul Kloos, Emmanuel Gay, Willem Jonker & Martin Giera

  3. Division of Immunoepigenetics, Department of Immunology and Cell Biology, Research Center Borstel, D-23845, Borstel, Germany

    Jörn Bullwinkel, Jeremy P Brown & Prim B Singh

  4. Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117, Berlin, Germany

    Jeremy P Brown & Prim B Singh

  5. Albert-Ludwigs-Universität Freiburg, BIOSS Centre for Biological Signalling Studies, Schänzlestrasse 18, 79104, Freiburg, Germany

    Maria Manukyan

  6. School of Natural Sciences and Psychology, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK

    Prim B Singh

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  1. Ebru Aydin
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  2. Dick-Paul Kloos
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  4. Willem Jonker
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  6. Jörn Bullwinkel
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  7. Jeremy P Brown
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  8. Maria Manukyan
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  9. Martin Giera
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  10. Prim B Singh
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  11. Reinald Fundele
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Corresponding authors

Correspondence to Prim B Singh or Reinald Fundele.

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Corresponding editor: Sanjeev Khosla

[Aydin E, Kloos D-P, Gay E, Jonker W, Hu L, Bullwinkel J, Brown JP, Manukyan M, Giera M, Singh PB and Fundele R 2015 A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects. J. Biosci. 40 1–14] DOI 10.1007/s12038-015-9520-x

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Aydin, E., Kloos, DP., Gay, E. et al. A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects. J Biosci 40, 325–338 (2015). https://doi.org/10.1007/s12038-015-9520-x

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