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Behavioral, physiological, and molecular mechanisms underlying reduced fertility in Nhlh2 knockout mice

Sarah A Johnson, University of Massachusetts Amherst


Successful reproduction in mammals requires the interaction of the reproductive and neuroendocrine systems. Nhlh2 is a basic helix-loop-helix transcription factor that is expressed in both the developing and adult neuroendocrine hypothalamus. Targeted deletion (N2KO) of Nhlh2 results in hypogonadism and obesity. In addition, male N2KO mice exhibit micropenis and reduction of male accessory sex organs and half of the female N2KO mice have thread-like uteri and small pale ovaries. Male N2KO mice have reduced levels of testosterone and FSH, and are infertile, while female N2KO are not completely infertile, but show a decline in reproductive potential as they age. In order to determine if the mechanisms underlying reduced fertility in N2KO male and female mice, we examined gamete number and competence, hormone concentrations and sexual behavior. We found that although sperm from KO mice is as functional as sperm from normal mice in IVF assays, N2KO mice have a 50% reduction in the number of mature sperm isolated from the caudal epididymis. Oocyte numbers in N2KO female is decreased with aging, but were competent for fertilization and development. Like N2KO males who are unresponsive to sexually receptive female mice, N2KO females show reduced lordosis when placed with an experienced male. Based on these findings we examined mRNA levels of estrogen receptor alpha (ERα) and progesterone receptor (PR), as they are important in the regulation of female and male sexual behavior. In wildtype (WT) female mice, a decline in ERα production is seen in response to the addition of estrogen. In N2KO females this decline is not observed; ERα levels are increased compared to WT females during proestrus. In male N2KO there is an increase in progesterone receptor mRNA levels. These data suggest that Nhlh2 may play a role in sexual behavior possibly via the regulation of ERα and progesterone receptor.

Subject Area

Molecular biology

Recommended Citation

Johnson, Sarah A, "Behavioral, physiological, and molecular mechanisms underlying reduced fertility in Nhlh2 knockout mice" (2005). Doctoral Dissertations Available from Proquest. AAI3163678.