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Endocrinology Vol. 140, No. 10 4739-4744
Copyright © 1999 by The Endocrine Society

ARTICLES

Pituitary Somatostatin Receptor (sst)1–5 Expression during Rat Development: Age-Dependent Expression of sst21

D. K. Reed2, A. I. Korytko2, R. W. Hipkin3, W. B. Wehrenberg, A. Schonbrunn and L. Cuttler

Departments of Pediatrics (D.K.R., A.I.K., L.C.) and Pharmacology (L.C.), Case Western Reserve University, Cleveland, Ohio; Department of Integrative Biology and Pharmacology (R.W.H., A.S.), University of Texas-Houston Medical Center, Houston, Texas; and College of Agriculture (W.B.W.), Forestry and Life Sciences, Clemson University, Clemson, South Carolina

Address all correspondence and requests for reprints to: Leona Cuttler, M.D., Department of Pediatrics, Rainbow Babies and Children’s Hospital, Room 737, Case Western Reserve University, 11100 Euclid, Cleveland, Ohio 44106. E-mail: lxc15{at}po.cwru.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The capacity of the pituitary to suppress hormone secretion in response to somatostatin (SRIF) is markedly age dependent. Immature pituitaries are relatively resistant to SRIF effects, and increasing sensitivity to SRIF with advancing age is believed to cause characteristic developmental changes in pituitary hormone secretion in mammals. However, the cellular mechanism(s) underlying this developmental pattern of response to SRIF are not understood. Because somatostatin receptors (ssts) are critical mediators of SRIF’s actions on target tissues, we investigated the expression of sst1, sst2, sst3, sst4, and sst5 messenger RNA (mRNA) in pituitaries of developing and mature rats. Animals were studied at embryonic day 19.5, and at postnatal days 2, 12, 30, 45, 70, and 1 yr; these ages correspond to major changes in circulating GH levels and pituitary responsiveness to SRIF. Pituitary levels of sst2 mRNA increased strikingly and progressively with advancing age after birth (F = 30.92, P < 0.0001). Compared with 2-day-old pituitaries, sst2 mRNA abundance rose 3.25-fold by 12 days of age and 6-fold by 70 days of age. Moreover, Western blot analysis indicated a marked increase in pituitary expression of sst2A protein with advancing age. By contrast, pituitary abundance of sst1, sst3, sst4, and sst5 mRNAs did not differ with age. To assess the role of endogenous SRIF in regulating perinatal sst2 gene expression, we also administered a well-characterized SRIF antiserum (or NSS as controls; 10 µl/10 g) sc daily from postnatal days 2 to 12 of life. Treatment with SRIF antiserum raised GH levels but did not alter pituitary sst2 mRNA abundance, compared with controls. Taken together, these data indicate that 1) the perinatal rat pituitary expresses the same complement of ssts as the adult pituitary; 2) expression of ssts is developmentally regulated in a highly subtype-specific manner; 3) pituitary sst2 mRNA and sst2A protein increase markedly and progressively with advancing age after birth; and 4) the perinatal rise in sst2 mRNA levels is unlikely to be regulated by endogenous SRIF. The finding of subtype-specific, developmentally determined sst expression indicates a novel and potentially fundamental mechanism of sst regulation, and suggests a molecular mechanism underlying developmental maturation in the capacity of the pituitary to respond to SRIF.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ACTIONS of somatostatin (SRIF) are initiated by its interaction with specific cell-surface receptors. Five distinct somatostatin receptor (sst) subtype genes have been cloned and characterized (1, 2, 3, 4). The five sst subtype genes are located on different chromosomes, and significant diversity in the structural and pharmacological properties of the ssts have been reported (2, 4, 5, 6). The sst subtypes also show distinct but overlapping tissue and cellular distributions and are thought to subserve unique functions (7, 8). Despite their distinctive properties and their importance in mediating SRIF actions, little is known about the regulation of the individual ssts during normal development.

The pituitary is a major target of SRIF action. Although all ssts are present in the mature pituitary, the roles of the different sst subtypes in mediating pituitary cell function are not fully understood. Physiologic responsiveness to SRIF is limited to somatotrophs, thyrotrophs, and lactotrophs. In somatotrophs, SRIF is the key inhibitor of GH release and is needed to establish normal GH secretory patterns. The suppressive action of SRIF on GH is thought to be mediated by sst2 and/or sst5. In the mature rat somatotroph, there is evidence that sst2 is the predominant mediator of SRIF’s inhibitory effect (2, 5, 9, 10). In humans, it has been suggested that both sst2 and sst5 regulate GH secretion (11). However, unlike the rat pituitary, there is evidence for a more prominent role of sst5 on GH secretion in human somatotroph tissue (12), suggesting possible species differences in sst function. SRIF is thought to inhibit TSH secretion (13, 14, 15), and this effect has been reported to involve sst5 in humans (12). The physiological role of ssts in regulating PRL is less clear (16, 17); under some experimental conditions, SRIF can reduce PRL secretion (18, 19), and it has been suggested that sst2 may mediate this action in human pituitaries (12).

Despite the marked suppressive effect of SRIF on GH secretion in the mature rat pituitary, both in vitro and in vivo studies demonstrate that the immature pituitary is resistant to GH inhibition by SRIF (20, 21, 22, 23); however, the underlying cellular mechanisms are not known. Developing pituitaries are also highly sensitive to the GH stimulatory effect of GH-releasing hormone (GHRH), compared with adults (24). These findings, together with the well-known observation that circulating GH levels are extremely elevated in immature mammals and decline with age after birth (24, 25, 26, 27, 28, 29, 30, 31, 32, 33), suggest that perinatal patterns of GH secretion reflect differential capacity of the immature pituitary to respond to the major hypothalamic regulatory peptides—GHRH and SRIF. Heightened responsiveness to GHRH may be due, at least in part, to elevated levels of GHRH-receptor gene expression during the perinatal period (34), and resistance to SRIF may reflect low levels of sst gene expression. The current study focuses on the hypothesis that ssts, the critical mediators of SRIF’s actions, are developmentally regulated. If so, differential expression of ssts may underlie the characteristic age-dependent responsiveness to SRIF and ontogeny of GH secretion. Therefore, the primary goal of this study was to determine pituitary gene expression of the five major sst subtypes during key phases of perinatal development and adult life.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and tissue preparation
Sprague Dawley rats (Zivic-Miller Laboratories, Inc. Zelienople, PA) were studied at the following ages: embryonic day 19.5 (21.5 day gestation); postnatal days 2, 12, 30, 45, 70; and 1 yr. These ages correspond to major changes in circulating levels of GH (24, 28, 29, 30, 31, 32), pituitary GHRH-receptor expression (34), and to developmental changes in the responsiveness of the pituitary to SRIF (20, 24). The day of birth was considered day 0, and animals were weaned on day 21. Males were studied at all ages except embryonic day 19.5 and 2 days of age, when both male and female pituitaries were used; there are not data to suggest gender differences in SRIF responsiveness and/or sst expression among perinatal pituitaries. All animal procedures were approved by the Institutional Committee of Animal Care and Use of Case Western Reserve University. All rats were housed in the Animal Resource Center at Case Western Reserve University and were provided standard rat chow and water ad libitum. Rats were killed at 1000–1100 h by rapid decapitation. Pituitaries were removed and stored on dry ice until processed. Total pituitary RNA was isolated by extraction with acid guanidinium isothiocyanate-phenol-chloroform (35) and quantified by spectrophotometry.

Sst subtype gene expression
Expression of sst subtypes was assessed by ribonuclease protection assays, using probes specific for each individual subtype, kindly provided by Drs. J. F. Bruno and M. Berelowitz (7). cRNA, labeled with [32P]-UTP (NEN Life Science Products, Boston, MA), was generated by in vitro transcription. Riboprobe preparation and ribonuclease protection assays were carried out with reagents supplied by Ambion, Inc. (Austin, TX). In each experiment, 20 µg total pituitary RNA from each age group were analyzed for sst1, sst2 and sst5; 30 and 40 µg from each age group were analyzed for sst3 and sst4, respectively. Probe specificity was confirmed using total RNA from tissue previously identified to contain or to not contain each sst subtype (7) and by incubation with and without RNase A-T1. Stable hybrids were resolved by electrophoresis through 8% polyacrylamide-7M urea gels. Results were quantified as cpm per unit area by radioimaging (AMBIS). Independent pituitary samples for each age were used in each experiment.

Western analysis of sst2A protein
To determine whether the developmental differences we observed in sst2 messenger RNA (mRNA) were also found for sst2A protein, we evaluated sst2A protein in 2, 12, 30, and 70 day-old rat pituitaries by Western analysis. Cell membranes were prepared as previously described for GH-R2 cells (36) and for rat pituitaries (37). Membranes (200 µg) were solubilized in 1 ml cold HEPES buffered saline (150 mM NaCl, 20 mM HEPES, 5 mM EDTA, 3 mM EGTA, 1 mM phenylmethylsulfonyl fluoride, pH 7.4) containing 4 mg/ml dodecyl-ß-maltoside (lysis buffer) on ice for 60 min at 4 C. The detergent lysates were clarified by centrifugation at 10,000 x g for 10 min, and the supernatants were incubated at 4 C for 90 min with 50 µl (packed volume) of washed wheat germ agglutinin-agarose (WGA; Vector Laboratories, Inc. Burlingame, CA) to adsorb glycosylated proteins. The wheat germ agglutinin-agarose was then washed vigorously with lysis buffer and the adsorbed glycoproteins were eluted with sample buffer (62.5 mM Tris-HCl, 2% SDS, 10% 2-mercaptoethanol (vol/vol), 6 M urea, and 20% glycerol, pH 6.8) at room temperature for 30 min and 60 C for 15 min. Membrane proteins were then separated by SDS-PAGE on a 7.5% polyacrylamide gel and transferred to PVDF membrane and immunoblotted with R2–88 antiserum as previously described (36).

Administration of SRIF antiserum
To determine whether endogenous SRIF influences expression of sst2 during early development, we also studied the effects of administration of SRIF antiserum on sst2 expression in perinatal rats. Rats were injected daily with a well characterized SRIF antiserum (10 µl/10 g; 38) or an equal volume of normal sheep serum (NSS, controls) from 2–12 days of age (n = 3 litters/group). On the tenth day of injection (2 h after injection), pituitaries were removed and placed on dry ice until processed for total RNA isolation as described above. Pituitaries from male pups in each litter were pooled into three independent samples before RNA isolation. Pituitary expression of sst2 mRNA was assessed and quantified as described above.

GH concentrations were determined by RIA (Amersham Pharmacia Biotech) in 10 µl of serum collected at the time of decapitation. Samples were stored at -20 C until assessed. The antiserum cross-reacts less than 0.3% with rFSH, rLH, rPRL, rTSH, and rACTH. The assay sensitivity is 0.16 ng/tube. All samples were run in duplicate.

Statistical analysis
Comparisons of receptor subtype expression among age groups were evaluated by ANOVA followed by Duncan’s multiple range test. Abundance of mRNA for each sst subtype was expressed relative to mRNA levels in 2-day-old rats in the same experiment (2d = 1). Data were log transformed before post-hoc analysis. Comparisons of sst2 expression and serum GH levels in control and SRIF antiserum-treated rats were evaluated by Students t test. A P value of less than 0.05 was equated with a significant difference.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Pituitary sst subtype expression of immature and mature rats
Pituitary expression of sst2 mRNA was markedly age-dependent (F = 30.92, P < 0.0001; Fig. 1Go). Levels of sst2 mRNA were low in pituitaries of fetuses and 2-day-old animals. Thereafter, pituitary sst2 expression rose progressively with advancing age until adulthood. Sst2 levels in fetuses were approximately one-third those of 2-day-olds. Sst2 mRNA abundance rose steeply in the immediate postnatal period, increasing 3.25-fold in 12-day-olds compared with 2-day-olds. By 70 days of age, pituitary sst2 mRNA levels were 6-fold greater than those in equal amounts of pituitary RNA from 2-day-olds. Pituitaries of perinatal and mature animals also expressed sst1, sst3, sst4, and sst5 mRNA. However, unlike sst2, there were no significant ontogenic changes in expression of these subtypes at the age groups studied (sst1, F = 1.19, n.s.; sst3, F= 0.96, n.s.; sst4, F= 1.92, n.s.; sst5, F = 2.32, n.s.; Fig. 2Go, a–d).



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  		Figure 1. Expression of sst2 mRNA in pituitaries of immature and adult rats. Expression of sst2 in the rat pituitary was markedly age-dependent (P < 0.0001). Levels of sst2 mRNA were low in pituitaries of fetuses and 2-day-old animals, and rose with advancing age until adulthood. In each experiment, the data were normalized against pituitary sst2 expression in 2-day-olds, which was assigned a value of 1. The upper panel shows results (mean and SEM) of three independent experiments. Means with the same letter superscript do not significantly differ. The lower panel shows a representative experiment. P, Probe not treated with RNase A-T1.

 


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  		Figure 2. Expression of sst1, sst3, sst4, and sst5 mRNAs in rat pituitary. In contrast to sst2 expression, pituitary expression of sst1(a), sst3(b), sst4(c), and sst5(d) mRNAs were similar in all age groups. The figure shows the results (mean and SEM) of independent experiments. In each experiment, the data are normalized against pituitary expression of the designated sst in 2-day-olds, which was assigned a value of 1.

 
Immunoblot analysis of sst2A protein
To assess expression of sst2A protein, Western blots were performed on pituitary tissue from 2, 12, 30, and 70-day-old rats. A single broad band, characteristic of the glycosylated sst2A receptor (36, 37), was observed in all samples. Interestingly, the receptor from 2-day-old rats migrated at a slightly lower apparent molecular weight than the receptor from older rats, suggesting that the sst2A might be less heavily glycosylated in immature animals. Sst2A protein abundance increased most dramatically between 2 and 12 days, but continued to increase until 70 days (Fig. 3Go), paralleling the findings for sst2 mRNA.



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  		Figure 3. Western blot analysis of sst2A immunoreactivity in rat pituitary tissue. Crude membrane proteins from GH-R2 cells (GH; 2.5 µg) and lectin-purified membrane proteins (200 µg) from 2, 12, 30, or 70-day-old rats were separated on a 7.5% SDS polyacrylamide gel and electrophoretically transferred to PVDF membrane. The membrane was then incubated with a 1:10,000 dilution of anti-sst2A R2–88 antiserum. A representative experiment is shown; molecular size markers (in kDa) are indicated on the left.

 
Effects of SRIF antiserum on pituitary sst2 expression
Because there is evidence that SRIF production increases with age (30, 39, 40) and that SRIF may modulate its own receptor(s) (41, 42), we examined the role of endogenous SRIF secretion as a potential determinant of the observed developmental regulation of sst2 using an immunoneutralization protocol. We used a well-characterized SRIF antiserum (38) to passively immunoneutralize endogenous SRIF during the time of steepest rise in postnatal pituitary sst2 expression. Perinatal rats received SRIF antiserum, or the equivalent volume of nonimmune serum (controls) for 10 days. The SRIF antiserum was effective in immunoneutralizing endogenous SRIF, as serum rGH concentrations were significantly higher (1.8-fold; P < 0.004) than controls. However, pituitary sst2 mRNA abundance did not differ between SRIF antiserum-treated and control animals (t = 1.8, p = n.s.; Fig. 4Go).



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  		Figure 4. SRIF antiserum did not alter the developmental rise in sst2 expression. The figure shows pituitary sst2 mRNA abundance in three groups of rats treated with antiserum to SRIF and three groups of rats treated with an equal volume of nonimmune serum (NSS; controls). Pituitary sst2 mRNA abundance did not differ between SRIF antiserum-treated and control animals (t = 1.8, P = n.s.).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The ssts are critical in mediating both the physiological actions of SRIF and the therapeutic effects of somatostatin analogs (1, 2, 3, 4, 43, 44). Several lines of evidence suggest that the regulation of ssts differs according to subtype, including the finding of tissue-dependent expression (2, 7, 43, 44, 45, 46, 47, 48). Although the pituitary is a key target of SRIF, little is known about the regulation of individual sst subtypes in normal pituicytes. In light of clear age dependence in pituitary responsiveness to SRIF that is unexplained, and early speculation that perinatal resistance to SRIF might reflect low numbers of somatostatin receptors (39), we examined gene expression of each sst subtype in pituitaries of developing and mature rats.

The current data provide compelling evidence that pituitary expression of ssts is developmentally determined in a subtype-specific manner. Pituitary expression of sst2 mRNA rises markedly with advancing age after birth. By contrast, pituitary abundance of sst1, sst3, sst4, and sst5 mRNAs does not differ with age. While the potential for a developmental increase in sst3 and sst5 mRNA exists, based on an upward trend in expression of both isotypes with age that did not reach statistical significance (see Fig. 2Go, b and d), the magnitude of the increases are much less than that observed for sst2. Earlier work indicated that both immature human (12) and rat (49) pituitaries express ssts. The current data extend these observations by analyzing sst subtype expression throughout development in rat pituitary, and by demonstrating subtype-specific maturational regulation of sst mRNAs. Recent evidence indicates that sst subtypes are also expressed selectively in other organs during early development [e.g. brain (50)], leading to the suggestion that specific ssts play a role in the maturation and function of developing organs.

The relative resistance of the perinatal pituitary to SRIF is well documented. SRIF fails to inhibit (or only partially inhibits) GH secretion from perinatal pituitaries, whereas SRIF markedly suppresses GH release by mature pituitary cells (21, 22, 23, 51). Furthermore, maximal resistance to SRIF coincides with elevated circulating GH concentrations during the perinatal period (24, 28, 30). These findings have long suggested that maturation of the pituitary’s capacity to respond to SRIF contributes to characteristic mammalian ontogenic changes in circulating GH, but the underlying mechanisms of resistance to SRIF have not been elucidated.

Sst2 may play an important role in mediating age-dependent pituitary responsiveness to SRIF. Our findings indicate that pituitary expression of both sst2 mRNA and protein increase with age. There is considerable evidence that sst2, alone or in combination with sst5, mediates the inhibitory actions of SRIF on somatotrophs (46, 52). Although sst2 is expressed in other pituitary cell types as well (37, 53, 54, 55), somatotrophs comprise approximately half of pituitary cells (56); therefore, the developmental changes in pituitary sst2 are likely to reflect changes in somatotrophs (although other pituicytes may also be involved). Taken together, the current findings strongly suggest that relatively low sst2 gene expression and low sst2A protein expression may contribute to resistance of the perinatal pituitary to SRIF, and that rising expression of sst2 contributes to the increasing responsiveness of pituitaries to SRIF with maturation.

The mechanism(s) directing expression of sst2 in the developing rat pituitary are not known. Given the established influence of hypothalamic hormones on expression of their pituitary receptors and reports that SRIF pretreatment of GH cell lines can alter sst levels (3, 41, 42), we postulated that the rise in pituitary sst2 expression with advancing age may result from increased endogenous SRIF secretion. Evidence for SRIF secretion during early development is based on several findings. First, SRIF has been detected in rat brain and hypothalamus as early as embryonic days 7 and 14, respectively (57). Second, the fetal rat hypothalamus secretes SRIF in vitro as early as day 16 of embryonic life (58). Third, some reports indicate SRIF secretion in vivo as early as postnatal day 1 (59). Finally, SRIF production by the hypothalamus rises between days 2 and 28 after birth (39, 40), and the hypothalamic concentration of SRIF shows an inverse correlation with serum GH concentrations during this time (21, 30). Yet, we found no effect of SRIF antiserum administration (daily from postnatal day 2 to 12) on sst2 expression compared with NSS controls. The absence of an effect on sst2, despite effectiveness of the antiserum in causing serum GH levels to rise, suggests that the observed age-dependent increase in sst2 expression is likely not mediated by endogenous SRIF. Taken together, the current results suggest that endogenous SRIF does not play a major role in determining the rise in pituitary sst2 expression during early development. The age-dependent increase in pituitary sst2 expression may therefore be mediated by developmental changes in a currently unidentified external stimulus or by intracellular events intrinsic to somatotroph maturation.

In summary, the current findings indicate that there is a marked increase in both pituitary sst2 gene and sst2A protein expression with advancing age after birth, and that maturation of sst2 expression in the perinatal period is unlikely to be caused by endogenous SRIF. Pituitary expression of sst1, sst3, sst4, and sst5 is not age dependent. The finding of subtype-specific, developmentally determined expression of ssts indicates a novel and potentially key mechanism for sst regulation and suggests a cellular mechanism underlying the known differential capacity of immature and mature pituitaries to respond to SRIF.


   Footnotes
 
1 This work was supported, in part, by the National Institutes of Health Grants DK-40221 and DK-32234. The results were presented, in part, at the 5th International Pituitary Congress, 1998. Back

2 These authors contributed equally to this work. Back

3 Partially supported by a postdoctoral fellowship from the Juvenile Diabetes Foundation. Back

Received April 5, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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