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Engrailed homeobox protein 2 (EN2) is a homeodomain-containing transcription factor that regulates developmental patterning of the midbrain and cerebellum, controlling processes such as neuron specification, synaptogenesis, and foliation[1][2][3][4]. It acts downstream of fibroblast growth factor 8 (FGF8) and determines the regionalization of the neural tube, with important functions in both embryonic neural circuitry development and adult brain organization[1][4]. Aberrant expression of EN2 is linked to neurodevelopmental disorders, including autism spectrum disorders and structural brain anomalies[4]. Additionally, EN2 is overexpressed and secreted in several tumors, especially prostate cancer, where it serves as a highly specific and sensitive urinary biomarker for noninvasive diagnosis[2][3]. Beyond its canonical role as a transcriptional regulator, secreted EN2 can be taken up by surrounding cells and may alter the tumor microenvironment, indicating a broader impact on cell-cell signaling in disease contexts[3].
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