New Mutations at the Imprinted Gnas Cluster Show Gene Dosage Effects of Gsα in Postnatal Growth and Implicate XLαs in Bone and Fat Metabolism but Not in Suckling
New Mutations at the Imprinted Gnas Cluster Show Gene Dosage Effects of Gsα in Postnatal Growth and Implicate XLαs in Bone and Fat Metabolism but Not in Suckling
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DOI：
10.1128/mcb.06174-11
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发表时间：
2012-03-01
影响因子：
5.3
通讯作者：
Peters, Jo
中科院分区：
文献类型：
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作者：
Eaton, Sally A.;Williamson, Christine M.;Peters, Jo
印迹Gnas簇参与肥胖、能量代谢、进食行为和生存能力。尚未确定父系表达的蛋白XL α s、XLN 1和ALEX或双倍剂量的母系表达的Gs α对表型的相对贡献。在这项研究中，我们已经产生了两个新的突变体（Ex 1A-T-CON和Ex 1A-T）的Gnas簇。Ex 1A-T-CON的父系遗传导致Gs α印记的丢失，导致断奶前生长迟缓，随后追赶生长。Ex 1A-T的父系遗传导致Gs α印记的丧失以及XLas和XLN 1表达的丧失。这些小鼠具有严重的断奶前生长迟缓和不完全追赶生长。它们是完全可行的，可能是因为哺乳未受损，不像突变体，其中所有已知的父系表达的Gnasxl蛋白（XL α s，XLN 1和ALEX）的表达受到损害。我们认为，ALEX的损失是最有可能负责先前观察到的哺乳缺陷。在成年人中，Ex 1A-T的父系遗传导致代谢率增加以及归因于XL α s损失的脂肪量、瘦素和骨矿物质密度减少。据我们所知，这是第一份描述XL α在骨代谢中作用的报告。我们认为XL α s参与了骨和脂肪细胞代谢的调节。
The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XL alpha s, XLN1, and ALEX or a double dose of maternally expressed Gs alpha to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gs alpha, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gs alpha and loss of expression of XLas and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XL alpha s, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XL alpha s. This is, to our knowledge, the first report describing a role for XL alpha s in bone metabolism. We propose that XL alpha s is involved in the regulation of bone and adipocyte metabolism.