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

Ebru Aydin1, Dick-Paul Kloos, Emmanuel Gay

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

Journal of Biosciences
|May 13, 2015
PubMed

Insights

Reduced CBX3 protein causes severe postnatal mortality in mice due to placental insufficiency and impaired thermoregulation. This highlights the critical role of CBX3 in mammalian development and survival.

Area of Science:

  • Mammalian genetics
  • Developmental biology
  • Epigenetics

Background:

  • Mammals possess three Heterochromatin Protein 1 (HP1) isotypes: HP1 beta (CBX1), HP1 alpha (CBX3), and HP1 gamma (CBX5).
  • HP1 proteins are encoded by the Cbx1, Cbx3, and Cbx5 genes, respectively.
  • A hypomorphic allele in the Cbx3 gene (Cbx3hypo) leads to severe postnatal mortality, with approximately 99% of homozygotes dying before weaning.

Purpose of the Study:

  • To investigate the underlying causes of severe postnatal mortality in mice with reduced CBX3 protein levels.
  • To elucidate the role of CBX3 in placental development, nutrient transport, and neonatal thermoregulation.

Main Methods:

  • Analysis of Cbx3hypo/hypo conceptuses and placentas during late gestation.
  • Quantitative assessment of placental size and vascularization.
  • Gene expression analysis (mRNA transcripts) for growth and transport-related genes.
  • Biochemical analysis of newborn Cbx3hypo/hypo pups, including blood glucose, liver glycogen, and brown adipose tissue (BAT) lipid content.
  • Measurement of Ucp1 gene expression in BAT.

Main Results:

  • Cbx3hypo/hypo conceptuses exhibited significantly reduced size and placental haplo-insufficiency.
  • Placentas showed reduced mRNA transcripts for genes involved in growth regulation and amino acid/glucose transport.
  • Narrower blood vessels were observed in the placental labyrinth of Cbx3hypo/hypo individuals.
  • Newborn pups were hypoglycemic, with depleted liver glycogen and near-complete loss of stored lipids in BAT.
  • A 10-fold reduction in the expression of the BAT-specific Ucp1 gene was noted.

Conclusions:

  • The severe postnatal mortality in Cbx3hypo/hypo mice is likely caused by a combination of factors.
  • Placental growth and transport defects lead to smaller neonates.
  • Impaired non-shivering thermogenesis due to reduced Ucp1 expression contributes to mortality.
  • CBX3 is crucial for normal placental function and neonatal adaptation to extrauterine life.

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