Cdkn1c (p57 Kip2 ) is the major regulator of embryonic growth within its imprinted domain on mouse distal chromosome 7

Abstract

BackgroundCdkn1c encodes an embryonic cyclin-dependant kinase inhibitor that acts to negatively regulate cell proliferation and, in some tissues, to actively direct differentiation. This gene, which is an imprinted gene expressed only from the maternal allele, lies within a complex region on mouse distal chromosome 7, called the IC2 domain, which contains several other imprinted genes. Studies on mouse embryos suggest a key role for genomic imprinting in regulating embryonic growth and this has led to the proposal that imprinting evolved as a consequence of the mismatched contribution of parental resources in mammals.ResultsIn this study, we characterised the phenotype of mice carrying different copy number integrations of a bacterial artificial chromosome spanning Cdkn1c. Excess Cdkn1c resulted in embryonic growth retardation that was dosage-dependent and also responsive to the genetic background. Two-fold expression of Cdkn1c in a subset of tissues caused a 10–30% reduction in embryonic weight, embryonic lethality and was associated with a reduction in the expression of the potent, non-imprinted embryonic growth factor, Igf1. Conversely, loss of expression of Cdkn1c resulted in embryos that were 11% heavier with a two-fold increase in Igf1.ConclusionWe have shown that embryonic growth in mice is exquisitely sensitive to the precise dosage of Cdkn1c. Cdkn1c is a maternally expressed gene and our findings support the prediction of the parental conflict hypothesis that that the paternal genome silences genes that have an inhibitory role in embryonic growth. Within the IC2 imprinted domain, Cdkn1c encodes the major regulator of embryonic growth and we propose that Cdkn1c was the focal point of the selective pressure for imprinting of this domain.

Analysis of imprinted messenger RNA expression in deceased transgenic cloned goats

“…These results were consistent with reports of gene expression in cloned piglets (Jiang et al, 2007). Lack of expression found in mouse research indicated that CDKN1C resulted in the excessive growth of the placenta and fetus, but its overexpression also induced fetal growth retardation and even death (Andrews et al, 2007;Tunster et al, 2011). The DLK1 higher expression levels were proportional to the deterioration of hepatocarcinogenesis (Huang et al, 2007;Jin et al, 2008).…”

Dysregulation of methylation and expression of imprinted genes in oocytes and reproductive tissues in mice of advanced maternal age

“…Aberrant methylation patterns of three maternally expressed imprinted genes (Cdkn1c, Grb10, and Kcnq1) were observed in fetal tissues obtained from aged mice. A two-fold increase in Cdkn1c transcript abundance can cause a 10-30 % reduction in fetal growth [40]. The decrease in Cdkn1c methylation we observed in the current experiment should result in overexpression of the gene and would thus contribute to the fetal growth restriction in aged mice that we observed; however, aberrant gene expression of Cdkn1c was not detected.…”

Genomic imprinting in development, growth, behavior and stem cells

“…2B). One protein-coding gene from this cluster that drives the BWS phenotype is CDKN1C, which makes a protein product that acts as a cell cycle inhibitor and growth restrictor; absence or mutation of CDKN1C promotes overgrowth (Andrews et al, 2007;Matsuoka et al, 1996). BWS is less frequently caused by activation of IGF2 and reduced H19 expression (typically through ICR deletions and an increase in methylation at the H19 promoter), although in these cases it is often accompanied by Wilms and other tumors (Choufani et al, 2013).…”