Abstract
BackgroundSuccessful reproductive efforts require the establishment of a situation favorable for reproduction that requires integration of both behavior and internal physiological events. TR4 nuclear receptor is known to be involved in male fertility via controlling spermatogenesis, yet its roles in regulating other biological events related to reproduction have not been completely revealed.MethodsMale TR4 knockout (TR4-/-) and wild type mice were used for the sexual behavior and penile dysfunction studies. Mice were sacrificed for histological examination and corresponding genes profiles were analyzed by quantitative RT-PCR. Reporter gene assays were performed.ResultsWe describe an unexpected finding of priapism in TR4-/- mice. As a transcriptional factor, we demonstrated that TR4 transcriptionally modulates a key enzyme regulating penis erection and neuronal nitric oxide synthese NOS (nNOS). Thereby, elimination of TR4 results in nNOS reduction in both mRNA and protein levels, consequently may lead to erectile dysfunction. In addition, male TR4-/- mice display defects in sexual and social behavior, with increased fear or anxiety, as well as reduced mounting, intromission, and ejaculation. Reduction of ER alpha, ER beta, and oxytocin in the hypothalamus may contribute to defects in sexual behavior and stress response.ConclusionsTogether, these results provide in vivo evidence of important TR4 roles in penile physiology, as well as in male sexual behavior. In conjunction with previous finding, TR4 represents a key factor that controls male fertility via regulating behavior and internal physiological events.
Highlights
Successful reproductive efforts require the establishment of a situation favorable for reproduction that requires integration of both behavior and internal physiological events
Our previous studies on characterization of Testicular nuclear receptor 4 (TR4)-/- mice found that heterozygote mice (TR4+/-) are indistinguishable with TR4+/+ mice [11], and this remains true in this current study that TR4+/, like TR4+/+, have no obvious defects
TR4 Comparing histological sections of penis tissue from a TR4+/+ mouse, a TR4-/- mouse without priapism, and a TR4-/mouse with priapism (Figure 2D-L), we found more red blood cells within the corpus cavernosa (CC), and corpus spongiosum(CS) (H & I vs G) and dorsal vein (DV) (K & L vs J) in TR4-/- tissue than in TR4+/+ tissue
Summary
Successful reproductive efforts require the establishment of a situation favorable for reproduction that requires integration of both behavior and internal physiological events. TR4 nuclear receptor is known to be involved in male fertility via controlling spermatogenesis, yet its roles in regulating other biological events related to reproduction have not been completely revealed. It has been linked to sickle cell disease as well as the use of vasoactive drugs, yet its molecular mechanism remains unclear. The cyclic nucleotide second messenger cGMP generated by activated guanylyl cyclase in penile smooth muscle cells regulates penile erection. These includes activation of guanylyl cyclase requires nitric oxide (NO), release in the penis upon sexual stimulation from neuronal and endothelial sources containing NO synthase (NOS), and respectively termed nNOS and eNOS. In the mice with TR4 knockout [11], penile priapism was one of the most striking phenotypes observed
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