RESULTS: Should Grb10 interact with Igf1r to regulate growth Grb10:Igf1r double mutant mice should be indistinguishable from Igf1r KO single mutants, which are around half normal size at birth. Instead, Grb10:Igf1r double mutants were intermediate in size between Grb10 KO and Igf1r KO single mutants, indicating additive effects of the two signalling proteins having opposite actions in separate pathways. Some organs examined followed a similar pattern, though Grb10 KO neonates exhibited sparing of the brain and kidneys, whereas the influence of Igf1r extended to all organs. An interaction between Grb10 and Insr was similarly investigated. While there was no general evidence for a major interaction for fetal growth regulation, the liver was an exception. The liver in Grb10 KO mutants was disproportionately overgrown with evidence of excess lipid storage in hepatocytes, whereas Grb10:Insr double mutants were indistinguishable from Insr single mutants or wild types.
CONCLUSIONS: Grb10 acts largely independently of Igf1r or Insr to control fetal growth and has a more variable influence on individual organs. Only the disproportionate overgrowth and excess lipid storage seen in the Grb10 KO neonatal liver can be explained through an interaction between Grb10 and the Insr. Our findings are important for understanding how positive and negative influences on fetal growth dictate size and tissue proportions at birth.
结果:Grb10是否应该与Igf1r相互作用以调节生长Grb10:Igf1r双突变体小鼠应该与Igf1rKO单突变体没有区别,出生时大约是正常大小的一半。相反,Grb10:Igf1r双突变体大小介于Grb10KO和Igf1rKO单突变体之间,表明两种信号蛋白在不同途径中具有相反作用的加性效应。检查的一些器官遵循类似的模式,尽管Grb10KO新生儿表现出大脑和肾脏的保留,而Igf1r的影响扩展到所有器官。类似地研究了Grb10和Insr之间的相互作用。虽然没有一般证据表明胎儿生长调节的主要相互作用,肝脏是个例外。Grb10KO突变体中的肝脏不成比例地过度生长,有证据表明肝细胞中脂质储存过多,而Grb10:Insr双突变体与Insr单突变体或野生型没有区别。
结论:Grb10在很大程度上独立于Igf1r或Insr的作用来控制胎儿的生长,并且对个体器官的影响更加可变。只有在Grb10KO新生儿肝脏中看到的不成比例的过度生长和过量的脂质储存可以通过Grb10和Insr之间的相互作用来解释。我们的发现对于理解胎儿生长的正面和负面影响如何决定出生时的大小和组织比例非常重要。