Atp8a1, a member of the P4-ATPase family, is a phospholipid flippase crucial for maintaining the asymmetric distribution of phospholipids, like phosphatidylserine (PS) and phosphatidylethanolamine, across lipid bilayers in eukaryotic cells [4,6,8,9]. This function is essential for normal cell function and survival, and is involved in various cellular processes such as membrane trafficking, cell signaling, and apoptosis [4,5,6,7].

Global Atp8a1 knockout mice studies showed that it is dispensable for spermatogenesis and male fertility, as mutant mice had normal sperm count, motility, and no major histologic defects in testis and epididymis [1]. However, Atp8a1 deletion in hematopoietic stem cells (HSCs) led to increased proliferative activity, associated with hyperleukocytosis, enhanced repopulation capability, and increased sensitivity to 5-FU-induced apoptosis. This was due to decreased PTEN protein levels and activation of PI3K-AKT-mTORC1 signaling [2]. In neurons, loss of ATP8A1 recapitulated the defect in synaptic vesicle mobilization at high frequency seen with loss of adaptor protein AP-3, indicating its role in high-frequency neurotransmitter release [3]. Atp8a1 deficiency in mice was also associated with PS externalization in hippocampal cells, leading to delayed hippocampus-dependent learning [8].

In conclusion, Atp8a1 plays diverse roles in maintaining normal cellular functions as revealed by gene knockout mouse models. These models have contributed to understanding its involvement in processes such as spermatogenesis, hematopoiesis, synaptic transmission, and hippocampal-dependent learning, providing insights into potential disease mechanisms related to these functions.