Phactr4, or phosphatase and actin regulator 4, is a member of the Phactr family of protein phosphatase 1 (PP1)- and actin-binding proteins. It is involved in multiple biological processes such as regulating cytoskeletal dynamics through coordinating PP1 and cofilin activity, and is associated with pathways like RHO/ROCK and integrin signaling [3,4,6]. It plays a crucial role in embryonic development, cell migration, and has implications in disease-related processes [5-8]. Genetic models, especially mouse models, have been valuable in studying its functions.

Disruption of the Phactr4 gene in mice leads to an embryonic gastrointestinal defect similar to human Hirschsprung disease due to colon hypoganglionosis, with mutant enteric neural crest cells (ENCCs) showing migration defects [3]. In the humpty dumpty (humdy) mouse mutant where Phactr4 is disrupted, there are failures in neural tube and optic fissure closure, resulting in exencephaly and retinal coloboma, along with abnormal cell-cycle progression [4]. In cancer, depletion of Phactr4 in cell lines leads to increased proliferation and transformation, and it is significantly deleted or mutant in many tumor subtypes, suggesting its role as a tumor suppressor [2,5]. In depression, up-regulation of Phactr4 in the CA1 hippocampus of rats is associated with the pathogenesis, while down-regulation alleviates depression-like behaviors [1].

In conclusion, Phactr4 is essential for regulating cytoskeletal dynamics, cell-cycle progression, and cell migration during development. Its dysregulation is linked to diseases such as Hirschsprung disease, certain birth defects, cancer, and depression. Mouse models with disrupted Phactr4 have been instrumental in uncovering its functions in these disease-related processes.