B6-hTFRC/Ube3a KO Mouse

The UBE3A gene encodes ubiquitin-protein ligase E3A, a critical enzyme in the ubiquitin-proteasome degradation system responsible for catalyzing substrate ubiquitination and regulating proteasomal clearance. This process is indispensable for maintaining proteostasis, particularly in neurons, where UBE3A governs synaptic plasticity, neural signaling, and neurodevelopment by modulating the levels of specific substrates. As an imprinted gene, UBE3A exhibits parent-of-origin-specific expression in brain neurons. The paternal allele is epigenetically silenced via cis-acting repression by a long noncoding antisense transcript (UBE3A-ATS) ^[1]. Consequently, only the maternal UBE3A allele is functionally active in neuronal populations. Loss of maternal UBE3A function disrupts ubiquitin-mediated proteolysis, leading to aberrant accumulation of neurodevelopmental regulators and subsequent dysregulation of synaptic maturation and circuit formation. These molecular deficits underlie the pathogenesis of Angelman syndrome (AS), a severe neurogenetic disorder. Patients with Angelman Syndrome commonly exhibit severe motor and intellectual developmental delays, ataxia, hypotonia, epilepsy, speech impairment, and distinctive facial features ^[2].

The Transferrin receptor (TFRC) gene encodes Transferrin Receptor 1 (TFR1), a protein that is expressed at low levels in most normal cells but shows increased expression in highly proliferative cells, such as basal epidermal cells, intestinal epithelium, and certain activated immune cells. Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), also express this receptor at high levels ^[3]. TFR1 plays a critical role in maintaining iron metabolism and homeostasis by facilitating receptor-mediated endocytosis of iron-bound transferrin (Tf) via Tf cycling, thereby promoting iron uptake ^[4]. Cellular iron deficiency can lead to apoptosis, while cellular transformation requires substantial iron to sustain proliferation, with iron overload contributing to tumor progression. The high expression of TFR1 in many tumors makes it a potential tumor marker, offering a target for therapies to inhibit tumor growth and metastasis ^[3]. Moreover, TFR1 is implicated in anemia and iron metabolism disorders. Studies have shown that elevated TFR1 expression in cardiomyocytes is associated with exacerbated inflammation in myocarditis patients ^[5].

The B6-hTFRC/Ube3a KO mice are generated by crossing B6-hTFRC(CDS) mice with Ube3a KO mice. These mice can be used for studying the pathogenesis of Angelman syndrome (AS), developing related therapeutic approaches, and conducting preclinical research on TFRC-targeted drugs.