Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The preoptic area of the mammalian forebrain is a critical substrate for the development and maintenance of many sexually dimorphic behaviors relevant to reproduction. Normal development of the male rodent brain requires completion of two processes: (1) masculinization-induction of the male phenotype, and (2) defeminization-removal of the female phenotype. Both processes, although distinct, are largely directed by the same steroid, estradiol. Whether estradiol achieves both ends via the same or separate mechanisms has been unknown. Here, we report that prostaglandin-E(2) (PGE(2)) acting downstream of estradiol, is necessary and sufficient to masculinize sexual behavior but does not affect defeminization of sexual behavior or maternal behavior. Moreover, the volume of the sexually dimorphic nucleus of the preoptic area predicts defeminization of sexual behavior, but not masculinization of sexual behavior. Another sexually dimorphic cellular endpoint regulated by estradiol, spinophilin protein expression in the mediobasal hypothalamus, was not affected by PGE(2). Thus, PGE(2) is a key divergence point in the downstream actions of estradiol to simultaneously masculinize and defeminize sexual behavior.
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PMID:Prostaglandin-E2: a point of divergence in estradiol-mediated sexual differentiation. 1612 5

The prostaglandin E2 (PGE2) mediates estradiol-induced masculinization of sexual behavior in the rat during a perinatal sensitive period. PGE2 induces formation of dendritic spines on preoptic area (POA) neurons and this synaptic pattern change is associated with the ability to express male sexual behavior as an adult. Whether PGE2 is released from astrocytes or neurons in the developing POA is unknown. To further understanding of how PGE2 induces dendritic spine formation at the cellular level, we have explored the PGE2 receptor subtype mediating this response. There are four receptors for PGE2, EP1, EP2, EP3 and EP4, each having unique but interacting signal transduction profiles. Treatment of newborn female rats with the EP receptor agonists iloprost, butaprost and sulprostone indicated that stimulation of both the EP2 and EP3 receptors significantly increased spinophilin, a protein whose levels positively correlate to the presence of dendritic spines and masculinization of the POA. Use of antisense oligonucleotides against the mRNA for each receptor reveals that either EP2 or EP3 receptor knockdown reduces spinophilin in PGE2- or estradiol-treated females, whereas reducing EP1 or EP4 receptor levels by the same means has a smaller but also significant effect. A developmental profile of EP receptor expression indicates EP1 in particular is elevated for the first few days of life, corresponding to the critical period for masculinization, whereas mRNA levels for the other three receptors remain relatively constant.
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PMID:Exploration of prostanoid receptor subtype regulating estradiol and prostaglandin E2 induction of spinophilin in developing preoptic area neurons. 1740 63

Sex differences in brain morphology underlie physiological and behavioral differences between males and females. During the critical perinatal period for sexual differentiation in the rat, gonadal steroids act in a regionally specific manner to alter neuronal morphology. Using Golgi-Cox impregnation, we examined several parameters of neuronal morphology in postnatal day 2 (PN2) rats. We found that in the ventromedial nucleus of the hypothalamus (VMN) and in areas just dorsal and just lateral to the VMN that there was a sex difference in total dendritic spine number (males greater) that was abolished by treating female neonates with exogenous testosterone. Dendritic branching was similarly sexually differentiated and hormonally modulated in the VMN and dorsal to the VMN. We then used spinophilin, a protein that positively correlates with the amount of dendritic spines, to investigate the mechanisms underlying these sex differences. Estradiol, which mediates most aspects of masculinization and is the aromatized product of testosterone, increased spinophilin levels in female PN2 rats to that of males. Muscimol, an agonist at GABA(A) receptors, did not affect spinophilin protein levels in either male or female neonates. Kainic acid, an agonist at glutamatergic AMPA/kainate receptors, mimicked the effect of estradiol in females. Antagonizing AMPA/kainate receptors with NBQX prevented the estradiol-induced increase in spinophilin in females but did not affect spinophilin level in males.
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PMID:Glutamate AMPA/kainate receptors, not GABA(A) receptors, mediate estradiol-induced sex differences in the hypothalamus. 1744 89

Prostaglandin E2 (PGE2) mediates the organization of male rat sexual behavior and medial preoptic area (MPOA) neuroanatomy during a sensitive perinatal window. PGE2 is up-regulated in response to estradiol, and initiates a two-fold increase in dendritic spines densities on neurons. All the four receptors for PGE2 and EP1-4 are present in developing POA, a critical region controlling male sexual behavior. Previous studies explored that EP receptors are involved in PGE2-induction of neonatal levels of spinophilin protein, a surrogate marker for dendritic spine formation, but did not assess behavioral masculinization. Here, we used two approaches, suppression of EP receptor expression with antisense oligonucleotides and activation of EP receptors with selective agonists, to test which receptors are necessary and sufficient, respectively, for the effects of PGE2 on behavior and neuronal morphology. In female rats, neonatal treatment with antisense oligonucleotides against EP2 or EP4 but not EP1 or EP3 completely prevented the expression of adult behavior organized by PGE2 exposure. The effects of ONO-DI-004, ONO-AE-259-01, ONO-AE-248, and ONO-AE1-329 (EP1-4 agonists respectively) were equivalent to PGE2 treatment, which suggests activating any EP receptor neonatally suffices in masculinizing sex behavior. When given alone, not all EP agonists increased neonatal POA spinophilin levels; yet giving each agonist neonatally increased adult levels. Moreover, adult spinophilin levels significantly correlated with two measures of male sexual behavior. The body of evidence suggests that EP2 and EP4 are both necessary and sufficient for PGE2-induced masculinization of sex behavior, whereas EP1 and EP3 provide redundant roles.
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PMID:Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates. 1872 14

Prostaglandin E(2) (PGE(2)) mediates the masculinization of adult sex behavior in rats in response to the surge in serum testosterone at approximately birth. Measures of behavioral masculinization correlate with a twofold increase in spinophilin protein and the density of dendritic spines in the medial preoptic area (POA). Of the four receptors for PGE(2), EP(2) and EP(4) are required for the masculinization of behavior by PGE(2). EP(2) and EP(4) couple to G(s)-proteins, activating protein kinase A (PKA). By using H89 (N-[2-(p-bromo-cinnamylamino)-ethyl]-5-isoquinoline-sulfon-amide 2HCl) and Ht31, disruptors of PKA signaling, we have determined that PKA signaling is required for the masculinization of behavior by PGE(2). Glutamatergic signaling often mediates PGE(2) signaling; therefore, we tested whether inhibition of AMPA/kainate and metabotropic glutamate receptor (mGluR) signaling prevents PGE(2)-induced behavioral masculinization and whether activation of glutamate receptors mimics PGE(2). Females treated neonatally with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) plus LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] combined (AMPA/kainate and mGluR inhibitors, respectively) before PGE(2) did not exhibit as many mounts or intromission-like behaviors or initiate these behaviors as quickly as animals treated with PGE(2) alone. Animals neonatally treated with kainate, (+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) (type I mGluR agonist), or the two combined mounted as frequently and initiated mounting behavior as quickly as those given PGE(2). Ht31 does not prevent the masculinization of behavior by ACPD plus kainate cotreatment; rather, the coadministration of NBQX plus LY341495 prevents the forskolin-induced formation of POA dendritic spine-like processes. We conclude that PKA, AMPA/kainate, and metabotropic glutamate receptor signaling are necessary for the effects of PGE(2), that each receptor individually suffices to organize behavior, and that PKA is upstream of the glutamate receptors.
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PMID:Prostaglandin E2-induced masculinization of brain and behavior requires protein kinase A, AMPA/kainate, and metabotropic glutamate receptor signaling. 1984 15