Estradiol differentially regulates lipocalin-type prostaglandin D synthase transcript levels in the rodent brain: Evidence from high-density oligonucleotide arrays andin situhybridization

Abstract

Microarrays comprise an efficient approach to discovering large numbers of differentially expressed mRNA transcripts in the CNS resulting from changes in hormonal milieu. We used high-density oligonucleotide microarrays to examine the short-and long-term actions of estradiol (E2) on the transcriptomes from the medial basal hypothalamus and other brain regions of E2-treated (10 g) adult female mice. Our results have revealed several unanticipated gene regulations. Most striking is lipocalin prostaglandin D2 synthase (L-PGDS), which catalyzes the conversion of prostaglandin (PG) H2 to PGD2, a neuromodulator involved in a variety of functions, including sleep, pain, and odor responses. In situ hybridization revealed significant increases in L-PGDS expression in the arcuate and ventromedial nucleus of the medial basal hypothalamus compared with vehicle controls. The magnitude of these changes is Ϸ2-fold and suggests a modulatory role for PGD2 in E2-controlled neuroendocrine secretions and behaviors. Surprisingly, L-PGDS gene expression is reduced 2-fold after E2 treatment in the ventrolateral preoptic area (VLPO), the suspected site of action for the sleep-promoting effects of PGD2. Finally, whereas L-PGDS has been reported to be expressed primarily in oligodendrocytes of the adult rodent brain, we demonstrate, immunocytochemically, that L-PGDS is also expressed in a population of VLPO neurons. Thus, our data suggest the intriguing possibility that E2 modulation of L-PGDS plays a role in the regulation of sleep-wake states through hitherto unknown mechanisms in VLPO neurons and through hormone-dependent neuronal-glial cooperation.microarrays ͉ preoptic area ͉ oligodendrocytes ͉ estrogens ͉ arousal G onadal estrogens have wide-ranging effects in the central nervous system (CNS) of most adult mammals, including rodents and humans. These effects include but are not limited to the regulation of endocrine secretions from the anterior pituitary (1-4), sex-specific behaviors in rodents (5, 6), learning and memory (7-9), and neuroprotection (10-12). Estrogens are also known to regulate the expression of a number of different genes in the CNS (6). Despite this knowledge, we lack a complete understanding of estrogen-targeted genes in the CNS and how changes in their transcript levels may contribute to the myriad of neurobiological functions affected by estrogens.Microarray technology is a powerful method for assessing the changes simultaneously in thousands of gene transcripts in neuroendocrine systems (reviewed in ref. 13). It can reveal the orchestration of genomic changes taking place within the cells of the CNS and can lead to unanticipated discoveries of genomic alterations. We have been using high-density oligonucleotide arrays to elucidate the short-and long-term actions of estrogens on the transcriptomes from the medial basal hypothalamus (MBH) and other brain regions of female adult mice. Because the functional consequences of estrogens acting at the level of the MBH are well documented (see above), this region is an...

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“…72 Microarray results have been confirmed by Northern blot analysis and by in situ hybridization histochemistry. PGDS is a non-neuronal enzyme, 64 significantly involved in sleep.…”

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