The Nhlh2 transcription factor is required for female sexual behavior and reproductive longevity

Nhlh2 is a member of the basic helix-loop-helix (bHLH) transcription factor family and is expressed in developing and adult neuroendocrine tissues such as the pituitary and hypothalamus. Targeted deletion of Nhlh2 (N2KO) in mice results in hypogonadism and obesity. While gonadally intact male N2KO mice are infertile and lack male sexual behavior, female N2KO mice can become pregnant and carry litters to full term. Unlike normal females in which fertility averages 8-12 months with approximately one pregnancy per month, N2KO females have a shorter reproductive span with most females supporting only three to four pregnancies in a 9-month period. In addition, N2KO females exhibit abnormal estrous cycles characterized by a truncated estrus and a prolonged proestrus. We have found that while young female N2KO mice ovulate the same number of oocytes as normal females in response to exogenous hormones, the number of oocytes released by aged N2KO females is reduced over 50%. Interestingly, oocytes from N2KO females are equally competent for in vitro fertilization assays when compared to oocytes from similarly aged normal and heterozygous mice. We have further demonstrated that both young and old N2KO females show at least a 50% reduction in hormone-stimulated sexual behavior as measured by their lordosis quotient. This suggests that N2KO females show a lifelong behavioral hyporesponsiveness to exogenous steroid hormones accompanied by a reduction in reproductive longevity via reduced ovulation with aging. Potential gene regulatory mechanisms that involve the action of the Nhlh2 transcription factor on female fertility and sexual behavior are discussed.