Plagge Antonius, Gordon Emma, Dean Wendy, Boiani Romina, Cinti Saverio, Peters Jo, Kelsey Gavin
Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, CB2 4AT, UK.
Nat Genet. 2004 Aug;36(8):818-26. doi: 10.1038/ng1397. Epub 2004 Jul 25.
Genomic imprinting, by which maternal and paternal alleles of some genes have different levels of activity, has profound effects on growth and development of the mammalian fetus. The action of imprinted genes after birth, in particular while the infant is dependent on maternal provision of nutrients, is far less well understood. We disrupted a paternally expressed transcript at the Gnas locus, Gnasxl, which encodes the unusual Gs alpha isoform XL alpha s. Mice with mutations in Gnasxl have poor postnatal growth and survival and a spectrum of phenotypic effects that indicate that XL alpha s controls a number of key postnatal physiological adaptations, including suckling, blood glucose and energy homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl mutants and phenotypic comparison with Gnas mutants suggest that XL alpha s can antagonize Gs alpha-dependent signaling pathways. The opposing effects of maternally and paternally expressed products of the Gnas locus provide tangible molecular support for the parental-conflict hypothesis of imprinting.
基因组印记是指某些基因的母本和父本等位基因具有不同水平的活性，它对哺乳动物胎儿的生长发育具有深远影响。然而，印记基因在出生后的作用，尤其是在婴儿依赖母体提供营养期间的作用，目前还知之甚少。我们破坏了位于Gnas位点的一个父本表达转录本Gnasxl，它编码不寻常的Gsα异构体XLαs。Gnasxl发生突变的小鼠出生后生长和存活情况较差，并表现出一系列表型效应，这表明XLαs控制着许多关键的出生后生理适应过程，包括哺乳、血糖和能量稳态。Gnasxl突变体棕色脂肪组织中cAMP水平升高，以及与Gnas突变体的表型比较表明，XLαs可以拮抗Gsα依赖性信号通路。Gnas位点母本和父本表达产物的相反作用为印记的亲本冲突假说提供了切实的分子支持。
