Imprinted Grb10, encoding growth factor receptor bound protein 10, regulates fetal growth independently of the insulin-like growth factor type 1 receptor (Igf1r) and insulin receptor (Insr) genes
Imprinted Grb10, encoding growth factor receptor bound protein 10, regulates fetal growth independently of the insulin-like growth factor type 1 receptor (Igf1r) and insulin receptor (Insr) genes
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DOI：
10.1101/2024.01.24.576998
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发表时间：
2024-01
期刊：
影响因子：
5.4
通讯作者：
K. Moorwood;Florentia M. Smith;Alastair S. Garfield;Andrew Ward
中科院分区：
文献类型：
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作者：
K. Moorwood;Florentia M. Smith;Alastair S. Garfield;Andrew Ward
背景
出生时的最佳体型决定围产期存活率以及患肥胖、2型糖尿病和心血管疾病等常见疾病的长期风险。印记基因Grb10编码一种信号衔接蛋白，能够抑制受体酪氨酸激酶，包括胰岛素受体（Insr）和胰岛素样生长因子1型受体（Igf1r）。Grb10限制胎儿生长，以至于Grb10基因敲除（KO）小鼠出生时比野生型大约大25 - 35%。我们利用小鼠遗传学方法，对广泛持有的Grb10通过与具有高度保守的生长促进作用的Igf1r相互作用来影响生长这一假设进行检验。
结果
如果Grb10与Igf1r相互作用以调节生长，那么Grb10:Igf1r双突变小鼠应该与Igf1r KO单突变小鼠无法区分，后者出生时大约是正常体型的一半。然而，Grb10:Igf1r双突变小鼠的体型介于Grb10 KO和Igf1r KO单突变小鼠之间，这表明这两种在不同途径中作用相反的信号蛋白具有累加效应。所检查的一些器官也遵循类似模式，尽管Grb10 KO新生小鼠的大脑和肾脏未受影响，而Igf1r的影响则涉及所有器官。对Grb10和Insr之间的相互作用也进行了类似研究。虽然没有普遍证据表明其在胎儿生长调节方面存在主要相互作用，但肝脏是个例外。Grb10 KO突变体的肝脏过度生长不成比例，肝细胞中有脂质储存过多的迹象，而Grb10:Insr双突变小鼠与Insr单突变小鼠或野生型无法区分。
结论
Grb10在很大程度上独立于Igf1r或Insr来控制胎儿生长，并且对各个器官的影响更具可变性。只有在Grb10 KO新生小鼠肝脏中看到的不成比例的过度生长和脂质储存过多可以通过Grb10和Insr之间的相互作用来解释。我们的发现对于理解对胎儿生长的正负影响如何决定出生时的体型和组织比例非常重要。
Background Optimal size at birth dictates perinatal survival and long-term risk of developing common disorders such as obesity, type 2 diabetes and cardiovascular disease. The imprinted Grb10 gene encodes a signalling adaptor protein capable of inhibiting receptor tyrosine kinases, including the insulin receptor (Insr) and insulin-like growth factor type 1 receptor (Igf1r). Grb10 restricts fetal growth such that Grb10 knockout (KO) mice are at birth some 25-35% larger than wild type. Using a mouse genetic approach, we test the widely held assumption that Grb10 influences growth through interaction with Igf1r, which has a highly conserved growth promoting role. 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.