The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1
The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1
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DOI：
10.1101/2022.09.09.507324
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
I. Sandovici;D. Fernandez‐Twinn;Niamh Campbell;W. Cooper;Y. Sekita;I. Zvetkova;D. Ferland-McCollough;H. Prosser;L. Oyama;D. Cimadomo;Karina Barbosa de Queiroz;Cecilia S.K. Cheuk;Nicola M. Smith;R. Kay;Katharina Hoelle;N. H. Smith;S. Geyer;L. Reissig;W. Weninger;K. Siddle;A. Willis;M. Bushell;S. Ozanne;M. Constância
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作者：
I. Sandovici;D. Fernandez‐Twinn;Niamh Campbell;W. Cooper;Y. Sekita;I. Zvetkova;D. Ferland-McCollough;H. Prosser;L. Oyama;D. Cimadomo;Karina Barbosa de Queiroz;Cecilia S.K. Cheuk;Nicola M. Smith;R. Kay;Katharina Hoelle;N. H. Smith;S. Geyer;L. Reissig;W. Weninger;K. Siddle;A. Willis;M. Bushell;S. Ozanne;M. Constância
Mir 483是一种在胎盘哺乳动物中高度表达的保守microRNA，嵌入Igf 2基因中。在这里，我们揭示了控制机制和Mir 483在体内的生理功能，通过产生组成性功能丧失和过度表达小鼠。Mir 483的表达是印迹的，并且依赖于Igf 2启动子和Igf 2/H19印迹控制区。Mir 483的过度表达导致严重的妊娠中期胎儿，但不是胎盘，生长受限和晚期致死。通过使用诱导型转基因系统将Mir 483恢复至内源性水平来防止胎儿死亡。连续出生后Mir 483过度表达诱导生长发育迟缓，肝脂质含量升高，肥胖增加，局部和全身IGF 1水平降低和GH增加。通过IGF 1输注挽救生长表型。我们的研究结果为生长抑制microRNA与其生长促进宿主基因之间的新型功能性拮抗作用提供了证据，并表明Mir 483通过抑制IGF配体信号传导来限制过度组织生长。
Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.