Significance Without a fully developed and functioning initial segment, the most proximal region of the epididymis, spermatozoa do not undergo maturation, resulting in male infertility. The tumor suppressor phosphatase and tensin homolog (PTEN) was deleted from the initial segment, which resulted in changes in the activity of downstream signaling components that led to epithelial dedifferentiation and male infertility. Spermatozoa were normal upon leaving the testis, but as they progressed through the duct of the dedifferentiated initial segment, they developed angled flagella and a decrease in motility. These changes prevented spermatozoa from reaching and fertilizing an egg in the female reproductive tract. PTEN plays an essential role in maintaining normal initial-segment differentiation and function and, therefore, male fertility.