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The Transcription Factor VAX1 is Required for Normal Development and Function of GnRH Neurons and the SCN

Abstract

Infertility is becoming increasingly prevalent in our society, where one in six couples are faced with difficulties in conceiving. Fertility is tightly regulated by the hypothalamic-pituitary-gonadal axis, where the hypothalamic gonadotropin-releasing hormone (GnRH) neurons and the suprachiasmatic nucleus (SCN) are most vital. Here we identify a novel transcription factor, Ventral anterior homeobox 1 (VAX1), as a critical regulator of GnRH neuron development and SCN function. By the use of transgenic mouse models, we deleted Vax1 in GnRH neurons early in development leading to a 99% reduction in GnRH expression, resulting in delayed pubertal onset, hypogonadism, infertility in both sexes, and atypical estrous cyclicity in females. Furthermore, the deletion of Vax1 in the mature SCN significantly reduced expression of the key SCN peptide, VIP, which was associated with disrupted wheel-running activity. The weakened SCN output led to female subfertility, while the males were unaffected. These data together highlight the importance of VAX1 in both the developmental stage of fertility and its maintenance through adulthood.

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