Growth Factor Receptor‐Bound Protein 10‐Mediated Negative Regulation of the Insulin‐Like Growth Factor‐1 Receptor‐Activated Signalling Pathway Results in Cognitive Disorder in Diabetic Rats

Abstract

Growth factor receptor-bound protein 10 (Grb10) is a Src homology 2 domain-containing protein and one of the binding partners for several transmembrane tyrosine kinase receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1-R). The hippocampus, which is critical for cognitive functions, is one of the main distribution areas of Grb10 in the central nervous system. In recent years, diabetic encephalopathy has been defined as a third type of diabetes and the IGF1-IR pathway was shown to be critical for the neuropathogenic process of cognitive disorder in diabetes. However, the role of endogenous Grb10 in regulating the IGF1-IR pathway and neurobehavioural changes is not explicit. The present study aimed to determine the in vivo function of endogenous Grb10 in diabetic encephalopathy and the underlying mechanisms. Using stereotaxic surgical techniques and lentiviral vectors expressing specific short hairpin RNA, we could steadily knockdown Grb10 expression in the hippocampus. More importantly, we demonstrated that hippocampus-specific modulation of Grb10 protein levels led to a prominent remission of cognitive disorder, including improvements in both ultrastructural pathology and abnormal neurobehavioural changes. Our findings indicate that endogenous overexpression of Grb10 functions as a suppressor of the IGF1-IR pathway, which may represent an important mechanism for regulating cognitive disorder in diabetes.

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System

“…Furthermore, delivery of insulin directly into hippocampus enhances learning and memory in rats, while blockade of endogenous hippocampal insulin markedly impairs spatial learning and memory (McNay and Recknagel, 2011). Several genes in the insulin pathway are known to be involved in learning and memory; such as the insulin receptor ( Insr) (Zhao et al, 2004), the insulin-like growth factor 2 ( Igf2) (Chen et al, 2011), the Igf2 receptor (Igf2r) (Chen et al, 2011, Lee et al, 2015) , the ras-guanine nucleotide releasing factor 1 ( Rasgrf1 ) (Fernandez-Medarde et al, 2007) and the growth factor receptor-bound protein 10 ( Grb10 ) (Ma et al, 2013). Interestingly, the pleomorphic adenoma gene-like 1 ( Plagl1/Zac1 ) gene regulates a gene network involving Igf2, Igf2r, Grb10 and Rasgrf1 (Varrault et al, 2006, Hoffmann and Spengler, 2012, Charalambous et al, 2007).…”

GRB10 and E2F3 as Diagnostic Markers of Osteoarthritis and Their Correlation with Immune Infiltration

“…Grb10 plays a key role in the function of vascular smooth muscle cells by regulating the proliferation, migration, and inflammatory gene expression of these cells [30]. Another study reported that the expression of GRB10 in the hippocampus of diabetic rats is increased, impairing neural function and cognition by negatively regulating the insulin-like growth factor-1 receptor signaling pathway [31]. Moreover, the expression of insulin-like growth factor-1 is related to the proliferation, differentiation, and matrix synthesis of chondrocytes, which are essential in cartilage morphogenesis [32].…”

FGFR3 gene mutation plus GRB10 gene duplication in a patient with achondroplasia plus growth delay with prenatal onset

“…A previous study reported that endogenous GRB10 expression was increased in the hippocampus of rats with diabetic encephalopathy and that this increase might result in damaged nerve functions and cognitive impairments. In addition, the insulin/IGF1 signaling pathways have been implicated in dysregulated synaptic maturation and may play key roles in brain aging and dementia as well as learning and cognitive functions in rodent models [ 14 , 19 ]. In the present study, the IGF1 and IGFBP3 levels in the patient were far below normal levels, consistent with a model in which the duplication of GRB10 directly inhibits the phosphorylation of the IGF1R substrate and reduces the level of Grb10 expression to below normal limits, which may result in nervous system impairments such as growth delays and intellectual disabilities (ID) [ 23 ].…”