Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation.
Mice with maternal duplication of proximal Chromosome 11 (MatDp(prox11)), where Meg1/Grb10 is located, exhibit pre- and postnatal growth retardation. To elucidate the responsible imprinted gene for the growth abnormality, we examined the precise structure and regulatory mechanism of this imprinted region and generated novel model mice mimicking the pattern of imprinted gene expression observed in the MatDp(prox11) by deleting differentially methylated region of Meg1/Grb10 (Meg1-DMR). It was found that Cobl and Ddc, the neighboring genes of Meg1/Grb10, also comprise the imprinted region. We also found that the mouse-specific repeat sequence consisting of several CTCF-binding motifs in the Meg1-DMR functions as a silencer, suggesting that the Meg1/Grb10 imprinted region adopted a different regulatory mechanism from the H19/Igf2 region. Paternal deletion of the Meg1-DMR (+/DeltaDMR) caused both upregulation of the maternally expressed Meg1/Grb10 Type I in the whole body and Cobl in the yolk sac and loss of paternally expressed Meg1/Grb10 Type II and Ddc in the neonatal brain and heart, respectively, demonstrating maternalization of the entire Meg1/Grb10 imprinted region. We confirmed that the +/DeltaDMR mice exhibited the same growth abnormalities as the MatDp(prox11) mice. Fetal and neonatal growth was very sensitive to the expression level of Meg1/Grb10 Type I, indicating that the 2-fold increment of the Meg1/Grb10 Type I is one of the major causes of the growth retardation observed in the MatDp(prox11) and +/DeltaDMR mice. This suggests that the corresponding human GRB10 Type I plays an important role in the etiology of Silver-Russell syndrome caused by partial trisomy of 7p11-p13.
Shiura
Hirosuke
H
Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Nakamura
Kenji
K
Hikichi
Takafusa
T
Hino
Toshiaki
T
Oda
Kanako
K
Suzuki-Migishima
Rika
R
Kohda
Takashi
T
Kaneko-ishino
Tomoko
T
Ishino
Fumitoshi
F
D000818:Animals; D002880:Chromosomes, Human, Pair 11 / Q000378:metabolism*; D005260:Female; D051383:GRB10 Adaptor Protein / Q000235:genetics*; D020868:Gene Silencing; D018392:Genomic Imprinting; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice
C495959:Grb10 protein, mouse; D051383:GRB10 Adaptor Protein