Sh2b1-flox Mouse

Sh2b1, also known as SH2-B and PSM, is an intracellular adaptor protein. It belongs to the Src homology 2B (SH2B) family and contains characteristic SH2 and PH domains. Sh2b1 is crucial for signal transduction of several receptor tyrosine kinases and cytokine receptors associated with Janus kinases. It enhances leptin and insulin signaling, and thus is vital for energy balance, body weight regulation, and glucose metabolism [2,5].

Genetic deletion of Sh2b1 in mice leads to severe leptin and insulin resistance, hyperphagia, obesity, and type 2 diabetes [2]. Neuron-specific Sh2b1 overexpression protects against diet-induced obesity and insulin resistance [2]. In an MPTP mouse model of Parkinson's disease, Sh2b1 deficiency exacerbates behavioural defects and neuronal apoptosis, while neuron-specific overexpression reverses these effects. Mechanistically, Sh2b1 promotes PLIN4 degradation via binding to HSC70, suppressing lipid peroxidation stress [1]. In the hippocampus, selective genetic ablation of Sh2b1 in inhibitory neurons, but not excitatory neurons, impairs working memory and behavioral flexibility in mice, influencing fluid intelligence in a metabolism-independent manner [3]. Also, deletion of Sh2b1 in the paraventricular hypothalamus (PVH) neurons or the DRN-projecting PVHSh2b1 subpopulation causes energy imbalance, obesity, and metabolic disorders [4].

In conclusion, Sh2b1 plays essential roles in metabolism-related processes and neurodegenerative and cognitive functions. Gene knockout mouse models have been instrumental in revealing its role in obesity, type 2 diabetes, Parkinson's disease, and fluid intelligence-related cognitive functions, providing insights into the underlying molecular mechanisms and potential therapeutic targets for these diseases.