Department of Life Sciences, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Present Address: Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Campus, Box 7633, Raleigh, NC, 27695, USA.
BMC Biol. 2024 Sep 30;22(1):221. doi: 10.1186/s12915-024-02018-5.
The growth factor receptor bound protein 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles for Grb10 and Grb14 in glucose-regulated energy homeostasis. Both Grb10 KO and Grb14 KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition, Grb10 strongly inhibits fetal growth such that at birth Grb10 KO mice are 30% larger by weight than wild type littermates.
Here, we generate a Grb7 KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this, Grb7 and Grb14 did not have a major role in influencing fetal growth, either alone or in combination with Grb10. At birth, in most respects both Grb7 KO and Grb14 KO single mutants were indistinguishable from wild type, while Grb7:Grb10 double knockout (DKO) were near identical to Grb10 KO single mutants and Grb10:Grb14 DKO mutants were slightly smaller than Grb10 KO single mutants. In the developing kidney Grb7 had a subtle positive influence on growth. An initial characterisation of Grb7 KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having a significantly smaller renal white adipose tissue depot and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller white adipose depots, without improved glucose clearance.
Grb7 and Grb14 do not have significant roles as inhibitors of fetal growth, unlike Grb10, and instead Grb7 may promote growth of the developing kidney. In adulthood, Grb7 contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.
生长因子受体结合蛋白 7（Grb7）家族的信号传导衔接蛋白包括 Grb7、Grb10 和 Grb14。每个都可以与胰岛素受体和其他受体酪氨酸激酶相互作用，其中 Grb10 和 Grb14 抑制胰岛素受体活性。在细胞培养研究中，它们介导包括细胞存活、增殖和迁移在内的功能。小鼠敲除（KO）研究揭示了 Grb10 和 Grb14 在葡萄糖调节的能量平衡中的生理作用。Grb10 KO 和 Grb14 KO 小鼠在外周组织中均表现出胰岛素信号增加，葡萄糖和胰岛素敏感性增加，清除葡萄糖负荷的能力略有增加。此外，Grb10 强烈抑制胎儿生长，以至于出生时 Grb10 KO 小鼠的体重比野生型同窝仔鼠重 30%。
在这里，我们生成了 Grb7 KO 小鼠模型。我们表明，在胎儿发育过程中，Grb7 和 Grb14 的表达模式各自与 Grb10 的表达模式重叠。尽管如此，Grb7 和 Grb14 都没有在单独或与 Grb10 一起影响胎儿生长方面发挥主要作用。出生时，在大多数方面，Grb7 KO 和 Grb14 KO 单突变体与野生型没有区别，而 Grb7:Grb10 双敲除（DKO）与 Grb10 KO 单突变体几乎相同，Grb10:Grb14 DKO 突变体比 Grb10 KO 单突变体略小。在发育中的肾脏中，Grb7 对生长有轻微的积极影响。对 Grb7 KO 成年小鼠的初步特征分析显示，能量平衡存在性别二态性影响，与野生型同窝仔鼠相比，雌性的肾脏白色脂肪组织储量明显较小，清除循环中葡萄糖的能力增强。雄性的空腹血糖水平升高，白色脂肪组织储量有变小的趋势，但葡萄糖清除率没有改善。
Grb7 和 Grb14 不像 Grb10 那样作为胎儿生长的抑制剂发挥重要作用，相反，Grb7 可能促进发育中肾脏的生长。在成年期，Grb7 对葡萄糖介导的能量平衡有细微贡献，这增加了所有三种衔接蛋白在生理调节胰岛素信号和葡萄糖处理方面的冗余可能性。
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