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

Ebru Aydin, Dick-Paul Kloos, Emmanuel Gay, Willem Jonker, Lijuan Hu, Jorn Bullwinkel, Jeremy P Brown, Maria Manukyan, Martin Giera, Prim B Singh, Reinald Fundele

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Mammals have three HP1 protein isotypes HP1 beta (CBX1), HP1 alpha (CBX3) and HP1 alpha (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 (Cbx3hypo) causes a severe postnatal mortality with around 99 percent of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3hypo/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 nonshivering themogenesis. We suggest that it is the small size of the Cbx3hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality.

Original languageEnglish
Pages (from-to)325-38
Number of pages14
JournalJournal of Biosciences
Volume40
Issue number2
Publication statusPublished - Jun 2015

Fingerprint

prenatal development
homeostasis
Homeostasis
Brown Adipose Tissue
brown adipose tissue
Genes
Alleles
Homozygote
homozygosity
alleles
placenta
Defects
Placenta
Mortality
energy
neonates
Growth
Tissue
Liver Glycogen
conceptus

Keywords

  • Adipose Tissue, Brown
  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • Chromosomal Proteins, Non-Histone
  • Female
  • Fetal Growth Retardation
  • Glycogen
  • Haploinsufficiency
  • Homeostasis
  • Hypoglycemia
  • Lipids
  • Liver
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Placenta
  • Pregnancy
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Aydin, E., Kloos, D-P., Gay, E., Jonker, W., Hu, L., Bullwinkel, J., ... Fundele, R. (2015). A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects. Journal of Biosciences, 40(2), 325-38.

A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects. / Aydin, Ebru; Kloos, Dick-Paul; Gay, Emmanuel; Jonker, Willem; Hu, Lijuan; Bullwinkel, Jorn; Brown, Jeremy P; Manukyan, Maria; Giera, Martin; Singh, Prim B; Fundele, Reinald.

In: Journal of Biosciences, Vol. 40, No. 2, 06.2015, p. 325-38.

Research output: Contribution to journalArticle

Aydin, E, Kloos, D-P, Gay, E, Jonker, W, Hu, L, Bullwinkel, J, Brown, JP, Manukyan, M, Giera, M, Singh, PB & Fundele, R 2015, 'A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects', Journal of Biosciences, vol. 40, no. 2, pp. 325-38.
Aydin E, Kloos D-P, Gay E, Jonker W, Hu L, Bullwinkel J et al. A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects. Journal of Biosciences. 2015 Jun;40(2):325-38.
Aydin, Ebru ; Kloos, Dick-Paul ; Gay, Emmanuel ; Jonker, Willem ; Hu, Lijuan ; Bullwinkel, Jorn ; Brown, Jeremy P ; Manukyan, Maria ; Giera, Martin ; Singh, Prim B ; Fundele, Reinald. / A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects. In: Journal of Biosciences. 2015 ; Vol. 40, No. 2. pp. 325-38.
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abstract = "Mammals have three HP1 protein isotypes HP1 beta (CBX1), HP1 alpha (CBX3) and HP1 alpha (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 (Cbx3hypo) causes a severe postnatal mortality with around 99 percent of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3hypo/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 nonshivering themogenesis. We suggest that it is the small size of the Cbx3hypo/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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AU - Gay, Emmanuel

AU - Jonker, Willem

AU - Hu, Lijuan

AU - Bullwinkel, Jorn

AU - Brown, Jeremy P

AU - Manukyan, Maria

AU - Giera, Martin

AU - Singh, Prim B

AU - Fundele, Reinald

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AB - Mammals have three HP1 protein isotypes HP1 beta (CBX1), HP1 alpha (CBX3) and HP1 alpha (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 (Cbx3hypo) causes a severe postnatal mortality with around 99 percent of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3hypo/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 nonshivering themogenesis. We suggest that it is the small size of the Cbx3hypo/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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