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Receptor Expression

MR expression has been reported in many tissues, such as in the epithelial cells of the kidney, colon, and in sweat glands, in non-epithelial cells of the heart, in adipose tissues (white and brown), in ovaries and testis.

From: Vitamins and Hormones, 2019

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Androgen Receptor

Estrogen Receptor

Progesterone Receptor

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Volume 1

April K. Binder, ... Kenneth S. Korach, in Knobil and Neill's Physiology of Reproduction (Fourth Edition), 2015

AR Expression in the Ovary

AR expression has been documented in the ovaries of multiple species, including mouse,373,450 rat,130,665–668 pig,669,670 sheep,671 cow,672 monkey,274,395,673–675 and human.395,625,676–679 The ovarian pattern of AR expression is well conserved among species, with levels being detectable throughout the stages of folliculogenesis except primordial follicles, with the highest expression in the granulosa cells of small preantral follicles, detectable expression in thecal/interstitial cells, and little to no expression in luteal cells (Table 25.6).

In the ovaries of multiple species, Ar/AR expression among growing follicles is inversely correlated with the extent of granulosa cell differentiation (Figure 25.25). A mechanism to decrease AR levels during follicle maturation is consistent with the need to reduce sensitivity to intrafollicular androgens, which rise to levels sufficient for aromatization to E2, as activating AR ligands are detrimental to the health of preovulatory follicles.680 In the ovaries of gonadotropin-stimulated rats, Testsuka and Hillier found that large antral follicles (>400 μm) exhibit a 2.75-fold higher level of Cyp19 expression relative to small follicles (<200 μm) but a 51% decrease in Ar expression.665 In rat ovaries, Ar expression is first apparent in early postnatal development in follicles of the preantral stage.681 In adult ovaries, decreasing AR immunoreactivity occurs during follicle differentiation; a decrease is first apparent in mural granulosa cells and then progresses in those cells closest to the antrum.667 Interestingly, cells composing the cumulus–oocyte complex of preovulatory follicles are believed to be the last to differentiate682 and maintain Ar expression throughout.667 This gradient of AR expression suggests that AR signaling correlates with the differentiation state of granulosa cells and follicle development.



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FIGURE 25.25. Relationship between expression of androgen receptor and aromatase (CYP19) during folliculogenesis.

(A) Expression of androgen receptor (Ar) and aromatase (Cyp19) expression in granulosa cells of small (∼200 μm), medium (200–400 μm), and large (>400 μm) follicles from immature rats after treatment with PMSG. Expression was quantified by RNase-protection assay and normalized to 18S rRNA (not shown); data are expressed as percentage of control values (SEM of three separate trials, each consisting of 8–10 animals). a, b: P <0.05; a, c: P <0.01 (by ANOVA with the Newman–Keuls test). (Source: Reproduced with permission from Ref. 491.) (B) Hypothetical model of androgen utilization during folliculogenesis. As follicular development progresses, thecal androgen production gradually increases. During the early stages of follicular differentiation, androgens act via androgen receptor (AR) to enhance FSH-induced differentiation, including the stimulation of Cyp19 expression. During the final stages of follicular development, androgens primarily serve as a substrate for CYP19-mediated E2 synthesis under stimulation by FSH and LH. This differential regulation of AR and CYP19 may be important in shifting androgen utilization from action to metabolism, thereby ensuring a healthy transition of a follicle from the early maturation to full maturation stage.

Source: Reproduced with permission from Ref. 683.

In primate and human ovaries, AR expression is also highest in the granulosa cells of small growing follicles, yet evidence of an inverse correlation with follicle differentiation is conflicting.625,674,675,678,684 Hillier et al. found AR immunoreactivity in the marmoset ovary is most abundant in granulosa cells of healthy pre- to small antral follicles and low or absent in preovulatory follicles of late follicular stage.674 In contrast, minimal differences in granulosa cell AR expression between preantral and large antral follicles are reported in rhesus monkey ovaries.675 Furthermore, healthy follicles at late stages of maturation in human ovaries are described to possess significant AR immunoreactivity.625,678,679 A recent report has suggested that AR expression is highest in small antral follicles and decreases as the follicle matures,685 suggesting that message levels may not correspond with AR protein levels in human follicles.

The regulatory factors for AR expression in the ovary are poorly understood. Small preantral follicles in rats maintain high AR levels after hypophysectomy indicating that gonadotropins are not required to induce AR expression.668 In fact, most evidence indicates that FSH or PMSG-induced differentiation of granulosa cells is the primary cause of reduced AR expression; Campo et al. demonstrated that PMSG treatment of rats leads to the replacement of high-affinity, low-capacity androgen binding sites by nonsaturable, low-affinity binding sites in the ovary.686 Similarly, immature rats treated with recombinant FSH over 48 h exhibit a 65% reduction in ovarian Ar mRNA levels and a further decrease when LH is included.668 However, neither FSH nor (BR)-cAMP affect Ar mRNA levels in cultured rat granulosa cells in vitro.665 This suggests that a paracrine interaction with theca and/or stromal cells is necessary for reduced Ar expression observed in granulosa cells. Interestingly, DHT also elicits a 20% reduction in Ar expression in rat granulosa cells in vitro that is prevented by co-treatment with FSH.665 In contrast, T reportedly has little effect on AR expression in rhesus monkey ovaries.675 There is increasing evidence that E2 may play a role in decreasing granulosa cell AR levels during follicle differentiation. Like DHT, E2 exposure of rat granulosa cells also leads to a 20% reduction in Ar transcripts, but this effect is unabated by FSH.665 Furthermore, granulosa cells retrieved from untreated hypophysectomized rats respond well to DHT plus FSH and exhibit increased Cyp19 expression accordingly; but the effect of DHT is lost in granulosa cells isolated from E2-primed hypophysectomized rats, suggesting that estrogen pretreatment decreases AR expression.442 Indeed, mature follicles in ERβ-null ovaries are reported to possess aberrantly high AR expression relative to similarly staged follicles in wild-type ovaries,450 supporting the idea that ER may act to decrease Ar expression. While the hormonal regulation of Ar expression is unclear, recent reports suggest that a member of the orphan nuclear receptor family, Nur77, is required for maximal Ar expression in murine ovaries. Nur77 regulates several steroidogenic enzymes in the ovary, including those involved in androgen synthesis,687 and recent reports demonstrate 20% reduction in Ar expression in the granulosa cells from Nur77-null mice.688 Dia and colleagues were able to show that NUR77 bound directly to the promoter regulatory region of the Ar gene in mouse granulosa cells, providing insight into one of the transcriptional factors necessary for maximal AR expression in the ovary.688

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Humoral Pathogenesis

T. Ernandez, ... T.N. Mayadas, in Systemic Lupus Erythematosus, 2016

Modulating the Expression of Activating and inhibitory FcγRs

FcγRs expression profile is influenced by cytokines. For instance, TNF upregulates FcγRIIA expression while downmodulating FcγRIIB and enhancing activating Ig-mediated signaling in immune cells.293 IL-10 also increases the expression of all ITAM-bearing FcγRs, while TGFβ, IFNγ, and macrophage stimulating factor upregulates in vitro FcγRIIIA.293,294 Other cytokines such as IL-4 and IL-13 reduce the expression of activating FcγRs.260,293 Altering the cytokine profile may be another effective therapeutic approach to modulate the balance between activating and inhibitory FcγRs and influence autoimmunity.260 Similarly, in the future, targeted delivery of antisense oligonucleotides or small molecules may enable the possibility to specifically modulate FcγRs profile in specific immune cells.260,295

Overall, these data suggest a strong potential for the development of new anti-inflammatory drugs that target the FcγR functions, by blocking the activating receptors, modulating the expression of the inhibitory FcγRIIB, or altering the activating signaling pathway of ITAM-bearing receptors. Much progress is expected in this field in the near future.

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Signalling events in natural killer cells

P.K. Epling-Burnette, ... Julie Y. Djeu, in Natural Killer Cells, 2010

NK receptor signalling in T-cells

KIR expression has also been reported on peripheral blood T-cell subsets; including the constitutive expression of KIR in γδ T-cells and inducible expression in effector memory CD8+ αβ T-cells. The mechanism governing the induction of these receptors on T-cells is unknown. KIRs have been postulated to be induced in response to self-antigen and increase with aging (Goronzy et al., 2005). The fact that tumour-specific CD8+ T-cells express KIR suggests that this receptor may be induced when MHC-class I is diminished within the tumour microenvironment (Gati et al., 2001). More-over, inhibitory KIR expression in the tumour environment is strongly associated with functional anergy.

While cytolytic NK and T-cells use distinct antigen receptors, these cells employ identical lytic processes to mediate tumour cell death. Release of perforin and granzyme B is critical not only in NK cell cytotoxicity but also for cytotoxicity mediated by T-cells (Fischer et al., 2007). Upon contact with tumour cells, the lytic granules in T-cells are mobilized toward the tumour cell, and perforin forms pores in the target cell membrane that then allows granzyme B and activated pro-apoptotic cysteine proteases, caspases, to induce apoptosis in the target cell. Granule exocytosis potently activates cell death in the target cells through the activation of these caspases, but can also cause target cell death in the absence of activated caspases, as shown in caspase-deficient mice (Smyth et al., 2005). The second pathway involves engagement of the Fas/CD95 death receptor on target cells by their cognate ligands FasL, expressed on NK cells, resulting in classical caspase-dependent apoptosis in the target cell (reviewed, (Smyth et al., 2005).

In addition to the role of NKR in cytotoxicity, KIR expression on memory T-cells may be important for T-cell survival (Young and Uhrberg, 2002). Engagement of KIRs with antibodies showed that KIR+ T-cells were more resistant to activation-induced cell death (AICD) in comparison to KIR- T-cells (Gati et al., 2003). Overexpression of recombinant KIR3DL in Jurkat T-cells showed that AICD was blocked by a process involving protein kinase C activation (Kwon et al., 2000). AICD is mediated by a pathway of receptor-mediated apoptosis involving the activation of a molecular death-inducing signalling complex (DISC), which involves ligation of Fas, recruitment of FADD and activation and autolytic cleavage of caspase 8 (Medema et al., 1997; Scaffidi et al., 1998). KIR+ cells activate an inhibitory molecule, c-FLIP, that inhibits the complex by binding to FADD and preventing the recruitment of caspase 8, which then blunts the apoptotic response (Gati et al., 2003). The role of c-FLIP has been documented in vitro (Miller and McCullar, 2001) and in vivo (Jansen et al., 2007) and it has been well established that this recruitment depends on phosphorylation of the inhibitory ITIM and recruitment of SHP-1 and SHP-2 (Verbrugge et al., 2006). Homozygous deletion of SHP-1 results in diminished AICD in activated T-cells and lymphoproliferation (Zhou et al., 1996).

Since KIR expression may play a complex biological role in T-cell function, studies were performed on KIR-HLA transgenic (Tg) mice (Cambiaggi et al., 1999). The selective expression of NK receptors were analyzed in wild-type mice, HLA Tg, KIR Tg, and KIR-HLA Tg mice. Splenocytes were analyzed for the cell surface expression of a marker of mouse memory CD44 in CD8+ T-cells. Absolute numbers of CD4+ and CD8+ T-cells were equivalent in control and KIR-HLA Tg mice but the size of the CD8+ memory compartment was increased in KIR-HLA mice. The memory cells were characterized by the absence of CD25 but maintained the ability to respond quickly to TCR ligation and possessed a higher number of cells capable of IFN-γ secretion in the peripheral blood. Interestingly, a two- to threefold increase in the number of cycling CD8+ T-cells was observed in KIR-HLA Tg mice compared to control mice. Taken together, these results showed that the in vivo engagement of inhibitory NKR with cognate MHC class I ligand leads to the selective accumulation of terminal memory cells. In humans, a syndrome of lymphoproliferation of T-cells or NK cells called lymphoproliferative disease of large granular lymphocytes (LDGL) or large granular lymphocyte (LGL) leukemia in association with myeloid bone marrow failure that is linked to functional KIR and dysregulated NCR expression. Dysregulation in the NKR signals may contribute to T-cell and NK-cell accumulation and disease pathogenesis (Epling-Burnette et al., 2004; Zambello et al., 2003).

Less is known about role of KIR expression and function in CD4+ T-cells (van Bergen et al., 2004). A few studies have shown memory KIR+ CD4+ T-cells to be present in healthy individuals, but the acquisition and expansion of these cells is more frequently detected in patients with acute coronary syndrome or rheumatoid arthritis. In these settings, KIR2DL2, KIR2DL3 and KIR2DS2 show preferential expression. To test the function of KIR in CD4+ T-cells, KIR2DL1 was transfected into Jurkat T-cells. Binding of the HLA-ligands for KIR2DL1 (HLA-C2-containing epitopes; see Table 7.1) in these transfected cells, led to co-stimulator function that resulted in IL-2 production but also to SHP-2 recruitment. KIR expression on CD4+ T-cell therefore has a highly pleotrophic effect on function that involves activation of lytic activity, secretion of cytokines, and enhancement of survival to improve the potential long-term accumulation of memory cells. Tumour-associated ligands of the activating NKG2D receptor can effectively stimulate T-cell responses at early but not late stages of tumour growth.

A critical determinant of NK and T-cell intracellular signalling is controlled by the Vav-1 molecule. The Vav molecule contains several complex structural domains including calponin homology (CH) domain, an acidic domain (AD), a pleckstrin homology (PH) domain, SH2, SH3, and cysteine-rich(CR) and praline-rich (PR) regions. Specific protein sub-domains of Vav-1 mediate distinct cellular processes (Billadeau et al., 2000). Examination of a CH-deficient mutant revealed that this domain is essential for NF-AT/AP-1-mediated transcription secondary to a defect in intracellular calcium mobilization. Expression of this mutant dramatically altered T-cell-mediated cytotoxicity. The PH domain mutant altered not only T-cell-dependent function but also impaired FcR-mediated killing by NK cells. In contrast, the PH domain mutant failed to regulate direct cytotoxicity, suggesting that the PH domain may differentially regulate distinct forms of killing. Mutation of three tyrosine residues within the AD revealed a negative regulatory site and hyperactive NF-AT/AP-1-mediated gene transcription and enhanced cell-mediated cytotoxicity. Together, these data demonstrate the importance of structural subdomains within the Vav-1 molecule that mediated domain-specific lymphocyte functions.

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Pharmacogenomics in Lung Cancer

George R. Simon, ... David R. Gandara, in IASLC Thoracic Oncology (Second Edition), 2018

EGFR Overexpression

EGFR expression refers to measurement of levels of receptor protein (either normal [wild-type] protein or abnormal [meaning from the mutated gene]) by IHC and is distinct from detection of an actual EGFR mutation. EGFR expression is detectable in approximately 80% to 85% of patients with NSCLC, although the levels of expression vary widely on a continual scale.21

Approximately 40% to 80% of NSCLC tumors overexpress EGFR.19 This wide range in the frequency of EGFR overexpression may be due to differences in the techniques used to determine EGFR overexpression, the criteria used to define overexpression levels, and the differences in study populations. Wild-type is the term used to describe EGFR that is overexpressed but not mutated. The result of overexpression is an overabundance of receptors that are available to interact with ligands. Wild-type EGFR becomes activated by binding to ligands. Ligand binding induces receptor dimerization, and the ligand-bound EGFR activates tyrosine kinase-mediated signaling pathways, leading to tumor proliferation, survival, and resistance to apoptosis.18

Tumor cells can overexpress EGFR as well as its ligands. Ligand overexpression increases EGFR dimerization, activation, and tyrosine kinase-mediated signaling, which can lead to uncontrolled tumor growth.22

EGFR overexpression is more common in squamous cell carcinoma and adenocarcinoma, and to a lesser extent in large-cell carcinoma.19 Although the clinical significance of overexpression in NSCLC remains controversial, some investigators have found that overexpression of EGFR is associated with more aggressive tumors, a poor clinical prognosis, and, in certain tumor types, the development of resistance to radiation and cytoxic agents.19

Among patients with NSCLC, wild-type EGFR is more common than mutated EGFR. Compared with mutated EGFR, patients who harbor wild-type EGFR show reduced benefit for EGFR tyrosine kinase inhibitors such as erlotinib and gefitinib. This may be because the wild-type EGFR typically sends a downstream signal that ultimately stimulates the growth of tumor cells that are dependent on the receptor, and gefitinib or erlotinib can modestly inhibit this relatively weak signal. In contrast, the mutated EGFR is constitutively activated with a prominent downstream signal that can be dramatically inhibited by gefitinib and erlotinib.18

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Localized Vulvodynia

Hope K. Haefner, in Diagnostic Gynecologic and Obstetric Pathology (Third Edition), 2018

Steroid Receptor Pathways

Steroid receptor expression and morphology in vulvar vestibular mucosa in women with provoked vestibulodynia have been studied. Increased expression of estrogen receptor alpha in the vestibular mucosa of patients with vestibulodynia has been found.87 Animal studies have shown that estrogen receptor subtypes are important for vanilloid receptor function.88 The vanilloid receptor is expressed by nociceptive fibers and is triggered by a variety of noxious stimuli, such as capsaicin, with subsequent release of neuropeptides, which may then induce neurogenic inflammation.89 An increase of vanilloid receptor VR-1 has been observed in vestibular biopsies from patients with provoked vestibulodynia.90

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Ovarian Hormones

Elie Hobeika, ... Carlos Stocco, in Hormonal Signaling in Biology and Medicine, 2020

3.3.1 Autoregulation of Ovarian Function by Progesterone

PR expression is rapidly induced by the LH surge in preovulatory follicles and in cultured granulosa cells of several species (Hild-Petito et al., 1988; Park and Mayo, 1991). In mice and rats, PR expression decreases rapidly after ovulation, and the receptor is not expressed in luteal cells throughout pregnancy (Park and Mayo, 1991; Natraj and Richards, 1993; Park-Sarge et al., 1995). In contrast, in primates, both PR-A and PR-B remain expressed in the CL, where PR-B is the predominant isoform (Duffy et al., 1997).

During the periovulatory window, along with the increase in PR expression, there is also a marked increase in progesterone synthesis in preovulatory granulosa cells. Progesterone synthesis increases enormously and is the primary hormone secreted by the luteal cells. Thus, progesterone concentrations during the follicular phase are lower than 1 ng/mL but increase in the luteal phase reaching up to 35 ng/mL. Specifically, levels peak during the midluteal phase and decline in the late luteal phase (Filicori et al., 1984).

Progesterone has been shown to play four major roles in the ovary: oocyte meiosis, ovulation, luteinization, and corpus luteum maintenance (Stocco et al., 2007). Progesterone appears to contribute to the reinitiation of meiosis in oocytes by disrupting gap junctions between cumulus cells (Shimada and Terada, 2002). The crucial role of progesterone on ovulation was demonstrated in PR knockout mice, which show impaired follicle rupture but are able to form CL-containing trapped oocytes (Lydon et al., 1996). Similarly, in monkeys, steroid ablation studies demonstrated that only progestins restored follicle rupture (Hibbert et al., 1996). The role of progesterone on the formation and maintenance of corpus luteum function has been clearly established (Stocco et al., 2007). Progesterone also appears to play a role before ovulation during follicle development. Thus, progesterone produced by the preovulatory follicle acts directly on granulosa cells promoting follicular growth and inhibiting apoptotic genes (Peluso, 2013).

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Neuroendocrinology

Maria Cristina De Martino, ... Steven W.J. Lamberts, in Progress in Brain Research, 2010

Distribution of ssts in pathological tissues

sst expression has been described in several pathological tissues, particularly in tumors and inflammatory tissues (Dalm et al., 2008; Reubi, 2003; Reubi et al., 1997).

High expression levels of sst have been found in NETs, which often originate from SS target tissues, such as pituitary adenomas, GEP-NETs (Fig. 2), paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTCs) and small cell lung cancers (SCLCs) (Grozinsky-Glasberg et al., 2008; Kvols et al., 1992; Lamberts et al., 1992; Reubi, 1997; Reubi et al., 1992a, 1992c; Schaer et al., 1997). Moreover, ssts have also been found to be expressed in other kinds of tumors, such as breast and prostate cancers, malignant lymphomas, meningiomas, astrocytomas, etc. (Lamberts et al., 2002a; Reubi et al., 1992b, 1992d; Vikic-Topic et al., 1995; Volante et al., 2008).

In the majority of human sst-expressing tumors, sst2 is the most abundantly expressed subtype and sst4 the least expressed. Moreover, a wide heterogeneity of sst subtype expression has been reported in different tumors and within the same tumor (Grozinsky-Glasberg et al., 2008; Hofland and Lamberts, 2003; Volante et al., 2008).

The expression of ssts has also been found in several non-tumoral pathologies, particularly in inflammatory and autoimmune disease, such as in the lesions of granulomatose disease and rheumatoid arthritis (RA) (Dalm et al., 2008; van Hagen et al., 2008).

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Cellular and Molecular Mechanisms of Hormone Actions on Behavior

J.G. Verbalis, in Hormones, Brain and Behavior (Second Edition), 2009

3.49.5.1 Localization of Brain AVP

V1aR expression in the CNS has been studied using receptor autoradiography and in situ hybridization histochemistry. V1aR binding in rats has been found in the lateral septum (LS), neocortical layer IV, hippocampal formation, amygdalostriatal area, bed nucleus of the striae terminalis (BNST), various hypothalamic nuclei, ventral tegmental area, substantia nigra, superior colliculus, dorsal raphe, nucleus of the solitary tract (NST), and inferior olive (Johnson et al., 1993). V1aR binding is moderate throughout the spinal cord, but binding is higher in the dorsolateral motoneurons in general and all motoneurons in the lumbar 5/6 levels, where innervation to the perineal muscles originates (Tribollet et al., 1997).

Neurons containing V1aR transcripts are found throughout the rat CNS, with prominent expression in the olfactory bulb, hippocampal formation, LS, suprachiasmatic nucleus (SCN), paraventricular nucleus (PVN), anterior hypothalamic area, arcuate nucleus, lateral habenula, ventral tegmental area, substantia nigra, superior colliculus, raphe nuclei, locus ceruleus, inferior olive, area postrema, and NST (Ostrowski et al., 1994; Szot et al., 1994).

V1bR was initially described in the anterior pituitary gland (Antoni, 1984), but since then V1bR immunoreactive cell bodies and V1bR mRNA have also been found in other areas of the rat brain, including the olfactory bulb, piriform cortical layer II, septum, cerebral cortex, hippocampus, PVN, SCN, cerebellum, and red nucleus (Lolait et al., 1995; Vaccari et al., 1998; Hernando et al., 2001; Stemmelin et al., 2005). In addition, in situ hybridization histochemistry studies using probes specific to V1bR found expression in hippocampal CA2 pyramidal neurons (Young et al., 2006). Importantly, to date V1bR distribution has not been mapped by receptor autoradiography due to the lack of a specific radiolabeled V1bR ligand. However, the recent synthesis of very selective agonists of V1b receptors should provide promising new tools for studies of the role of the V1b receptor in various species (Pena et al., 2007).

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Drosophila Models of Hereditary Spastic Paraplegia

Emily F. Ozdowski, ... Nina T. Sherwood, in Movement Disorders (Second Edition), 2015

73.3.1 Receptor Expression Enhancing Protein-1 (SPG31)

Because REEP1 (Receptor Expression Enhancing Protein-1) is one of the top three genes associated with HSP, it is surprising that it is little studied in Drosophila. In yeast and mammals, DP1/Yop1/REEP1 is an example of an intramembrane protein, similar to the reticulons with a hairpin loop that affects ER membrane curvature (Voeltz et al., 2006). On the basis of BLASTP comparisons to the 208-amino-acid isoform of human REEP1, there are two Drosophila polypeptides with significant sequence similarity: CG42678 (44% identity, 54% similarity) and CG5539 (18% identity, 30% similarity). Again, similar to the reticulons, one potential ortholog is widely expressed in brain and muscle (CG42678) whereas the other is restricted to testis (CG5539). Given the expression pattern and higher sequence similarity, CG42678 is likely the relevant ortholog, but no functional analyses of the nervous system have been performed. One study shows that RNAi knockdown of CG42678 driven by pannier-Gal4 results in viable flies with no bristle defects (Mummery-Widmer et al., 2009). Otherwise, REEP1 is new territory to expand with the Drosophila model.

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Olfaction & Taste

K. Touhara, in The Senses: A Comprehensive Reference, 2008

4.30.3.4 Ectopic Expression

OR expression is not restricted to olfactory sensory neurons. Expression of ORs in nonolfactory tissues was first observed in the male germ line (Parmentier, M. et al., 1992). Since then, ectopic OR transcripts have been found in a variety of tissues including the spleen and insulin-secreting cells (Blache, P. et al., 1998), lingual epithelial cells of the tongue (Durzynski, L. et al., 2005; Gaudin, J. C. et al., 2006), ganglia of the autonomic nervous system (Weber, M. et al., 2002), pyramidal neurons in the cerebral cortex of the brain (Otaki, J. M. et al., 2004), the colon (Yuan, T. T. et al., 2001), myocardial cells in developing heart (Drutel, G. et al., 1995; Ferrand, N. et al., 1999), the prostate gland (Yuan, T. T. et al., 2001), and erythroid cells (Feingold, E. A. et al., 1999). Polyclonal antibodies against an OR expressed in dog sperm bind specifically to the midpiece of the flagellum of mature sperm (Vanderhaeghen, P. et al., 1993; Walensky, L. D. et al., 1995). In other cases, the transcripts have been detected mainly by RT-PCR, and therefore, the expression level might be too low to be considered functional. Indeed, an RNase protection assay and microarray analysis estimated that a total of 50–70 OR genes are expressed in mouse testis (Vanderhaeghen, P. et al., 1997a; 1997b; Zhang, X. et al., 2004), whereas a careful in situ hybridization study revealed that only up to 10–20 OR genes were actually detected at a significant level (Fukuda, N. and Touhara, K., 2006) (Figure 5(a)). The testicular ORs are expressed in a subset of the seminiferous tubules, suggesting that they are expressed at specific stages during spermatogenesis (Fukuda, N. and Touhara, K., 2006). Phylogenetic analysis suggests that there is no unique characteristic sequence similarity among the testicular OR genes (Vanderhaeghen, P. et al., 1997b; Zhang, X. et al., 2004; Fukuda, N. and Touhara, K., 2006). Double-in situ hybridization experiments showed that, in contrast to olfactory neurons, more than one OR could be expressed in a single spermatogenic cell, indicating that the transcriptional regulation of OR genes in testis is distinct from that in the olfactory system (Fukuda, N. and Touhara, K., 2006) (Figure 5(b)).



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Figure 5. Expression of olfactory receptor (OR) genes in mouse testis. (a) In situ hybridization showing expression of an OR in a subset of the seminiferous tubules (asterisks). Scale bar = 0.1 mm. (b) Double-in situ hybridization of ORs showing two signals derived from two ORs in nuclei of round spermatids. Scale bar = 10 μm. Adapted from Fukuda, N. and Touhara, K. 2006. Developmental expression patterns of testicular olfactory receptor genes during mouse spermatogenesis. Genes Cells 11, 71–81, with permission from Blackwell Publishing.

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