Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A
Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A
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DOI：
10.1677/joe.1.06259
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发表时间：
2005-08-01
影响因子：
4
通讯作者：
Conover, CA
中科院分区：
文献类型：
--
作者：
Bale, LK;Conover, CA
妊娠相关血浆蛋白-A(PAPP-A)是一种胰岛素样生长因子结合蛋白(IGFBP)蛋白，通过裂解抑制的IGFBP-4和随后释放IGF多肽来激活受体，从而增加IGF的活性。PAPP-A基因定向破坏的纯合子小鼠出生时为比例矮小，在胎儿发育期间表现出迟缓的骨化。表型和体外数据支持一种模型，在该模型中，在胚胎发育期间降低IGF-II的生物利用度会导致生长迟缓和整体身体尺寸减小。为了验证在胚胎发育过程中增加IGF-II将克服生长缺陷的假设，将Pappa缺失的小鼠与Delta H19突变小鼠杂交，这些突变小鼠由于破坏IgfII印记而增加了IGF-II的表达，并导致胎儿过度生长。Delta H19突变小鼠出生时的大小是对照组的126%，Papp-A缺失小鼠的大小是对照组的74%。这些大小的差异在胚胎16.5天时就很明显。重要的是，双重突变体在大小和骨骼发育方面都与对照没有区别。在胚胎发育过程中设定的体型在出生后保持不变。因此，在胎儿发育过程中，IGF-II印迹的破坏和随之而来的IGF-II的升高与挽救PAPP-A缺失小鼠的矮小表型和成骨缺陷有关。这些数据提供了强有力的遗传证据，表明PAPP-A在确定IGF-II的生物利用度以实现最佳胎儿生长发育方面发挥着重要作用。
Pregnancy-associated plasma protein-A (PAPP-A), an insulin-like growth factor-binding protein (IGFBP) protease, increases insulin-like growth factor (IGF) activity through cleavage of inhibitory IGFBP-4 and the consequent release of IGF peptide for receptor activation. Mice homozygous for targeted disruption of the PAPP-A gene are born as proportional dwarfs and exhibit retarded bone ossification during fetal development. Phenotype and in vitro data support a model in which decreased IGF-II bioavailability during embryogenesis results in growth retardation and reduction in overall body size. To test the hypothesis that an increase in IGF-II during embryogenesis would overcome the growth deficiencies, PAPPA-null mice were crossed with Delta H19 mutant mice, which have increased IGF-II expression and fetal overgrowth due to disruption of IgfII imprinting. Delta H19 mutant mice were 126% and PAPP-A-null mice were 74% the size of controls at birth. These size differences were evident at embryonic day 16.5. Importantly, double mutants were indistinguishable from controls both in terms of size and skeletal development. Body size programmed during embryo development persisted post-natally. Thus, disruption of IgfII imprinting and consequent elevation in IGF-II during fetal development was associated with rescue of the dwarf phenotype and ossification defects of PAPP-A-null mice. These data provide strong genetic evidence that PAPP-A plays an essential role in determining IGF-II bioavailability for optimal fetal growth and development.