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Endocrinology Vol. 138, No. 7 2849-2855
Copyright © 1997 by The Endocrine Society

ARTICLES

Stimulatory Effect of Human, but not Bovine, Growth Hormone Expression on Numbers of Tuberoinfundibular Dopaminergic Neurons in Transgenic Mice1

Carol J. Phelps and Andrzej Bartke

Department of Anatomy, Tulane University School of Medicine (C.J.P.), New Orleans, Louisiana 70112; and the Department of Physiology, Southern Illinois University School of Medicine (A.B.), Carbondale, Illinois 62901

Address all correspondence and requests for reprints to: Dr. Carol J. Phelps, Department of Anatomy, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112. E-mail: cjphelps{at}mailhost.tcs.tulane.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Mice transgenic for heterologous and ectopic GH expression serve as models for studying the feedback effects of elevated nonregulated GH on hypothalamic hypophysiotropic neurons as well as on peripheral function. For example, hypothalamic somatostatin expression has been shown to be increased markedly in mice bearing either bovine (b) or human (h) GH transgenes. Human, but not bovine, GH has lactogenic properties in mice, and appears to stimulate PRL-inhibiting tuberoinfundibular dopaminergic (TIDA) neurons. The present study was designed to determine the effect of a lifelong excess of hGH on dopamine (DA) expression in and numbers of TIDA neurons. Male mice of four transgenic lines were examined. The transgenic animals bore constructs of either bGH or hGH fused to either metallothionein (MT) or phosphoenolpyruvate carboxykinase (PEPCK) promoters; brains of transgenic mice were compared morphologically with those of nontransgenic littermates. Formaldehyde-induced catecholamine histofluorescence and tyrosine hydroxylase (TH) immunocytochemistry were examined in alternate brain sections; cell number was quantified for TIDA neurons (area A12) and a nonhypophysiotropic diencephalic DA area, the medial zona incerta (A13). Body weights were higher (P < 0.01) in PEPCK-GH than in MT-GH transgenic mice, as were serum levels of heterologous GH in those lines. In MT-hGH, but not MT-bGH or PEPCK-bGH, transgenic mice, A12 perikaryal fluorescence was enhanced, and ME fluorescence was reduced compared with those in control animals. The reduced ME DA is likely to reflect stimulation of TIDA neurons, because A12 TH-immunoreactive neuron number was increased by 34% in MT-hGH mice compared with that in controls (P < 0.05). In mice bearing the PEPCK-hGH construct, A12 TH neuron number was increased 47% (P < 0.001) compared with that in littermate controls. There were no differences in A13 cell number among animals, and A12 cell numbers in mice expressing bGH did not differ from control values. These results suggest that although extremely high levels of circulating bGH do not stimulate TIDA neurons, lifelong high levels of hGH have a stimulatory and graded effect on developmental differentiation of these cells for TH and DA production, supporting the concept of PRL as a trophic factor for TIDA neurons.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GH AND PRL have specific dynamic feedback effects on the hypothalamic neurons that regulate their secretion, as has been shown by hypophysectomy and hormone replacement in adult animals. This feedback suppresses the production and release of stimulatory factors such as GH releasing hormone (GHRH) (1) and enhances the production of inhibitory factors such as somatostatin [somatotropin release-inhibiting hormone (SRIH)] (1, 2, 3, 4) and tuberoinfundibular dopamine (TIDA) (5, 6). Recent studies in this laboratory have shown that these feedback effects extend beyond dynamic regulation, to influence upon hypophysiotropic neuron differentiation and/or survival, when deficiency or excess of GH or PRL is genetic and lifelong, such as in spontaneous mutant or transgenic models. In spontaneous GH-deficient Ames dwarf mice (7), for example, not only is total GHRH messenger RNA (mRNA) expression enhanced, but the number of GHRH-immunoreactive neurons is increased (8). The GH and PRL deficiencies in spontaneous dwarf mice are also correlated with markedly reduced numbers of inhibitory SRIH (9, 10) and TIDA (11, 12) neurons. Conversely, transgenic mice that produce excess endogenous GH (13) show decreased hypothalamic GHRH mRNA (14) and markedly increased SRIH mRNA (15). Transgenic mice expressing heterologous [bovine (b) or human (h)] GH (16) exhibit increased hypophysiotropic SRIH mRNA and numbers of SRIH-producing neurons (17).

The effect of lifelong PRL excess on TIDA neurons has not been studied, and transgenic mice expressing excess PRL have not been available. However, there is evidence that hGH, which is lactogenic in rodents, has pronounced PRL-like properties in vivo when expressed in transgenic mice. This is evident at both peripheral targets, because nulliparous hGH transgenic females have been shown to lactate (18), and at the hypothalamic-pituitary level, where gonadotropin secretion is altered (19). Transgenic hGH, but not bGH, mice show decreased endogenous PRL levels, decreased median eminence (ME) dopmanine (DA), and increased DA turnover in ovariectomized females, indicative of TIDA neuron stimulation, such as occurs in response to PRL (20). Thus, although endogenous PRL production is reduced, these animals display some physiological symptoms of functional hyperprolactinemia, including stimulation of TIDA neurons (21). This study was designed to evaluate the effect of chronic lifelong excess hGH on DA expression and numbers of TIDA neurons. Transgenic hGH-expressing mice and transgenic animals expressing nonlactogenic bGH were compared with littermate controls. In addition, the effects of differing levels of heterologous GH expression were compared; transgenics carried hGH or bGH linked to either the metallothionein (MT) or the phosphoenolpyruvate carboxykinase (PEPCK) promoter. In the transgenic lines used for this study, mice bearing PEPCK-linked GH gene expressed higher levels of either heterologous GH (17).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and tissue preparation
Original transgenic mice were produced in the laboratory of Dr. T. E. Wagner by introduction of the entire GH structural gene fused with MT or PEPCK promoter into male pronuclei; the genotype of each original mouse was confirmed by dot blot analysis of DNA extracted from tail snips (22). The male mice evaluated in this study were produced by mating hemizygous transgenic males with normal C57Bl6/J x C3H/J hybrid females. Mice transgenic for bGH or MT-hGH were 4.0 ± 0.5 months of age, and PEPCK-hGH transgenic mice were 6.0 ± 0.5 months of age; transgenic and normal control mice were age-matched within type and were usually siblings. They were shipped from Southern Illinois University School of Medicine to Tulane University School of Medicine for evaluation. Deeply anesthetized (65 mg/kg BW pentobarbital, ip) mice were perfused transcardially with normal saline followed by either buffered 4% paraformaldehyde-0.5% glutaraldehyde (Faglu) fixative (23) or buffered 4% paraformaldehyde (PEPCK-hGH mice and normal littermates). Brains were removed and sectioned at 30 µm coronally on a Vibratome (Lancer Technical Products International, St. Louis, MO). The protocols for maintenance and killing of the animals were approved by both Southern Illinois University and Tulane University institutional animal care and use committees.

Histochemical methods
For qualitative assessment of catecholamines by formaldehyde-induced fluorescence, every sixth brain section (i.e. sections taken at 180-µm intervals) from each Faglu-perfused mouse was mounted and examined using narrow band excitation wavelengths (405–410 nm) and a barrier filter (460 nm) on a Nikon Optiphot microscope (Nikon Corp., Melville, NY) equipped for epiillumination. Native catecholamines are rendered fluorescent directly by this method, providing a means of qualitatively assessing the level of endogenous transmitter present in the tissue. For immunocytochemical detection of neurons expressing the DA synthetic enzyme tyrosine hydroxylase (TH), alternate brain sections were processed free floating for TH immunocytochemistry. Sections from animals perfused with Faglu were pretreated with sodium borohydride (1% in 0.1 M buffered, pH 7.5, phosphosaline for 30 min) to allow antibody access by reduction of glutaraldehyde-fixed linkages. Sections were incubated for 48 h in rabbit anti-TH (ETI, Piscataway, NJ) at a 1:3000 dilution and were processed further using biotinylated goat antirabbit IgG secondary antiserum and the avidin-biotin complex method (Vectastain ABC Kit, Vector Laboratories, Burlingame, CA). Immunostaining was visualized by hydrolysis of H2O2 (0.003%) using diaminobenzidine (0.02% in Tris buffer) as the precipitable chromogen. Sections from littermate controls and transgenics were stained at the same time, using identical reagent solutions. After immunostaining, sections were mounted in rostral to caudal order, dried, and coverslipped using Permount (Fisher Chemical, Pittsburgh, PA).

Cell counting
TH-immunostained cells were counted at 180-µm intervals (i.e. every sixth section) in two DA regions: area A13 perikarya in the medial zona incerta, and area A12, the TIDA neurons in the hypothalamic arcuate nucleus, according to the nomenclature established by Dählstrom and Fuxe (24). Although noradrenergic and adrenergic neurons are also TH immunoreactive, a number of pharmacological and immunocytochemical studies have shown areas A12 and A13 to be exclusively dopaminergic (reviewed in Ref. 25). In A13, neurons were counted in three to five sections for each animal; in area A12, cells were counted in six to nine sections, with larger numbers of sections in hGH transgenic mice. Total cell numbers were determined by correction for sampling frequency (six times); correction for cells missed or counted twice (26) was not performed, because the sampling interval greatly exceeded the average cell diameter of 13.3 µm (27).

Statistical analysis
GH levels (within genotype), body weights, and pituitary weights were assessed by one-factor ANOVA, followed by Student-Newman-Keuls post-hoc tests (SuperANOVA software, Abacus Concepts, Berkeley, CA), with values for all controls pooled. Cell counts in A12 and A13 were assessed by Student’s t test of littermate controls vs. each transgenic type, because of heterogeneity of variance among controls for this parameter. For both tests, P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Body and pituitary weights and GH levels
Body and pituitary weights and serum levels of heterologous GH for the MT-bGH, PEPCK-bGH, and MT-hGH transgenic mice evaluated in this study have been reported previously (17), but are presented together with data from PEPCK-hGH mice in Table 1Go for convenience. Values for all normal controls are grouped together because parameters given in the table did not differ among groups. Although the overall effect of mouse type on anterior pituitary weight was not significant, pituitary weight was decreased (P < 0.05) in PEPCK-hGH transgenic mice compared with that in controls. Serum hGH in PEPCK-hGH transgenic mice was not measured in the present study, but in a previous report (28), the level in male transgenics of this line was 491 ± 55 ng/ml compared with less than 0.5 ng/ml in control siblings. In overall analyses (ANOVA followed by Student-Newman-Keuls test) of the previously reported heterologous GH levels, mice bearing transgenes linked to the PEPCK promoter had higher levels of heterologous GH (P < 0.01 for both bovine and human) than mice bearing MT-GH constructs. In similar analyses, the effect of mouse type on weight was significant (F4,41 = 31.694; P < 0.0001), and body weights were higher in PEPCK-GH than in MT-GH transgenics for both bGH (P < 0.05) and hGH (P < 0.01).


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  		Table 1. Body, brain, and pituitary weights, and serum GH levels in transgenic mice

 
Catecholamine fluorescence in A12 and ME
DA fluorescence in A12 perikarya and ME terminals is shown in Fig. 1Go in representative coronal sections at a middle (rostral to caudal) level in representative normal (A), MT-bGH transgenic (B), PEPCK-bGH transgenic (C), and MT-hGH transgenic (D) mice. Qualitatively, the DA fluorescence was comparable for control (A) and bGH transgenic (B and C) mice, with faint perikarya and strong ME fluorescence intensity. In MT-hGH transgenic mice (D), the fluorescence pattern was reversed, in that DA perikarya were bright, and ME fluorescence was faint.



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  		Figure 1. Catecholamine fluorescence in midcoronal A12 and ME. A, Normal control mouse brain; B, MT-bGH transgenic mouse; C, PEPCK-bGH transgenic mouse; D, MT-hGH transgenic mouse. All coronal sections; original magnification. x10.

 
TH immunocytochemistry
Figure 2Go shows TH immunostaining at low magnification (original magnification, x4) to illustrate DA neurons in dorsal A13 (medial zona incerta) as well as in the ventral A12 TIDA neurons in representative coronal sections of normal control (A) and MT-hGH transgenic (B) mice. Qualitatively, immunostaining showed more TH-containing cells in area A12 in the hGH transgenic mouse (B) and comparable staining intensities and cell numbers in A13 of normal (A) and MT-hGH transgenic (B) mice.



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  		Figure 2. TH immunostaining in diencephalon of normal control (A) and MT-hGH transgenic mice (B). The dorsal (upper) cell group represents area A13 (medial zona incerta) dopaminergic cells; the ventral (lower) TH-positive cell groups are rostral A12 PRL-regulating TIDA neurons. Both sections are coronal; 30 µm; original magnification, x4.

 
Figure 3Go shows TH immunoreactivity in the A12 of normal control mice (A and C) compared with that in transgenics (B and D) for MT-hGH (A and B) and PEPCK-hGH (C and D) lines. The sections shown in A and B were immunostained simultaneously; the sections shown in C and D were also stained simultaneously, but separately from A and B. The background staining and signal to noise ratio obviously differed for the two types of transgenic mice; the analysis of cell counts, therefore, was separated.



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  		Figure 3. TH immunostaining in A12 neurons in hGH transgenic mice compared with littermate controls. A and B show littermates from the MT-hGH line; C and D represent mice from the PEPCK-hGH line. A and C show normal mice; B and D are sections from transgenics. All coronal sections; 30 µm; original magnification, x20.

 
Quantification of TH-immunoreactive neurons
Figure 4Go is a graph of TH-immunoreactive perikarya in A12 of all four GH-transgenic types compared with respective normal littermate controls. Numbers of detectable TH-positive perikarya were not different from those in normal littermates among MT-bGH or PEPCK-bGH transgenics, but were significantly increased in MT-hGH (P < 0.05) and PEPCK-hGH (P < 0.001) transgenic mice compared with numbers in normal littermates.



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  		Figure 4. Graph of TH-immunoreactive cell number in A12 (tuberoinfundibular) neuronal perikarya in four types of GH-transgenic mice compared with littermate controls. Cell numbers were higher than control values in MT-hGH (P < 0.05) and PEPCK-hGH (P < 0.001) mice.

 
Figure 5Go shows DA neuron numbers in DA area A13, comparing transgenic mice with respective controls. The number of TH-immunoreactive perikarya did not differ between transgenic and normal mice in any of the lines examined.



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  		Figure 5. Graph of TH-immunoreactive neuron number in the A13 (medial zona incerta) region in four types of transgenic mice expressing heterologous GH compared with that in normal nontransgenic littermate mice. No statistical differences were found between transgenic and control mice of any type.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The PRL-regulating DA neurons of the medial basal hypothalamus are affected by PRL feedback acutely (6) and developmentally (29). In mice with spontaneous and lifelong PRL deficiency due to Pit-1 mutations (30), as in Snell dwarfs (31, 32), or Pit-1-related mutations (33), such as the Ames dwarf (7), hypothalamic TIDA neurons are deficient in DA levels (34, 35) and reduced in number (11, 12). Studies of TIDA neuron development (35, 36) and of the effects of PRL replacement in Ames dwarf mice (37, 38) have indicated that the stimulatory feedback effect of PRL is necessary for the maintenance of TIDA neurons. The number of TH-immunoreactive A12 neurons actually declines during a critical period in postnatal development (36) unless exogenous PRL is supplied (37). Acutely increased PRL levels are correlated with increased DA turnover (6) and ME DA depletion in cases of extreme hyperprolactinemia (39) in rats; in mice, PRL-treated adults show increased DA and TH expression, but the number of TH-immunoreactive neurons is unaffected (38). The chronic developmental effect of elevated circulating PRL has not been studied previously, because models of lifelong increased PRL expression, such as transgenic mice carrying PRL constructs, have not been reported. However, transgenic mice expressing hGH can be used to study such an effect, because hGH has been shown to be lactogenic in mice at both peripheral target organs (18) and hypothalamic feedback (19, 20).

Expression of heterologous GH in transgenic mice has been detected in multiple ectopic sites; MT-GH is expressed variably in liver, testis, heart, lung, spleen, intestine, kidney, and brain (40), and PEPCK-GH is expressed in liver and kidney (22). GH secretion in such peripheral sites would not be expected to be influenced by hypophysiotropic peptides, because SRIH and GHRH would not reach peripheral targets at effective levels. In addition, the transgenic constructs used included only the GH structural gene, omitting upstream SRIH and GHRH regulatory regions, so that expression would be regulated primarily by factors affecting the MT and PEPCK promoters, such as metals and carbohydrate in the diet (22, 40). In the case of hGH, nonregulated production, therefore, would produce a state of functional hyperprolactinemia in mice. This status is certainly lifelong, because transgenes linked to the MT promoter begin expression during fetal development (40) and those linked to the PEPCK promoter begin at the time of birth (22). Thus, the onset of hGH expression in these transgenic mice begins before the normal onset of PRL production in mice at 7–8 days postnatally (35, 41).

The effect of lifelong elevated levels of a lactogenic hormone (hGH) on hypothalamic PRL-regulating neurons was investigated in this study. In mice expressing hGH, but not bGH, both DA and TH expression were enhanced qualitatively. That enhancement included the reduced fluorescence in ME of MT-hGH mice, which is likely to reflect increased DA turnover and release, as has been shown in hyperprolactinemic rats (39). Although PRL has been shown to affect DA turnover in hypothalamic neurons other than the TIDA group, PRL has been shown not to affect A13 neurons (42). In fact, long term hyperprolactinemia has been reported to have a neurotoxic effect on TIDA neurons (43), but the present results contradict such an effect. In terms of immunocytochemically detectable cells, the number of TH-expressing TIDA neurons was elevated in hGH, but not bGH, transgenic mice. The numbers of TIDA neurons in the mice of the present study are somewhat lower than have been reported for other strains (12); significant strain differences in this population have been noted previously (44). The results support the lactogenic effects of hGH on hypothalamic neurons in mice (20) and extend the effect to one on developmental differentiation of hypophysiotropic neurons; lifelong elevated levels of PRL (hGH) lead to elevated numbers of TIDA neurons. Such an effect is precedented. In PRL-deficient mice, the number of TIDA neurons has been shown to decrease from a normal complement after 21 days postnatally (36), but this decrease is prevented when PRL is replaced beginning at 12 days of age, before the onset of the decline (37). In addition, hypophysiotropic SRIH neuron number and total mRNA have been shown to be elevated markedly in transgenic mice expressing either bGH or hGH (17). Taken together, these studies indicate that fetal or early postnatal changes in PRL or GH secretion can affect not only levels of hypophysiotropic factor expression, but also numbers of extant neurons. The possible neurobiological phenomena occurring include postnatal prevention of cell death and prenatal or early postnatal recruitment of hypothalamic neurons to a dopaminergic phenotype. Because treatment of normal mice with PRL beginning at 12 days of age does not increase TIDA neuron number (37), the present results suggest that the effects of hGH on TIDA neurons in transgenic mice occur earlier in development. Differentiating these effects will require developmental studies in the transgenic animals.

These findings are corroborated by those of an earlier study (45) in which plasma PRL levels were decreased in MT-hGH male mice, and morphological studies of the pituitaries of MT-hGH male mice revealed indexes of lactotroph suppression (46). In addition, in ovariectomized MT-hGH transgenic compared with ovariectomized normal (wild-type) mice, PRL levels were decreased, and increased DA turnover indicated an activation of TIDA neurons (20). In another study (47), however, castrated MT-hGH transgenic mice showed no differences from controls in plasma or pituitary PRL levels or in DA turnover in the hypothalamus. In a previous study of PEPCK-hGH transgenic mice (28), plasma PRL levels were depressed, and pituitary weights were reduced in intact males, as in this study, but hypothalamic DA turnover was not different from that in controls. The present morphological evidence would suggest increased TIDA neuronal activity that would correlate with reduced endogenous PRL and pituitary size.

In a study of SRIH expression in transgenic mice expressing heterologous GH (17), SRIH mRNA level and cell number increased to the same degree, regardless of the heterologous GH level related to species (bovine or human) or promoter (MT vs. PEPCK). In the present study, higher levels of hGH in mice bearing the PEPCK-hGH construct, as opposed to the MT-hGH transgene, were associated with higher numbers of TH-immunoreactive TIDA neurons. Thus, alterations in the levels of heterologous GH differentially affect SRIH-producing, compared with TIDA, neurons.

The mechanism accounting for the effect of hGH, or even of mPRL, on TIDA neurons has yet to be elucidated. Direct feedback effects of GH or PRL on respective hypophysiotropic neurons would require localization of appropriate receptors on these neurons. There is evidence that hGH binds to PRL as well as GH receptors in rodents (48), but specific binding of hGH to receptors on hypothalamic PRL-regulating neurons in mice has not been reported. In rats, PRL receptors have been located in the medial basal hypothalamus by in situ hybridization (49) and autoradiographic immunocytochemistry (50), but the neurotransmitter phenotype of cells expressing the PRL receptor has not been reported. Receptors for GH have been localized to SRIH neurons (51), but in the arcuate nucleus appear to be located predominantly on neuropeptide Y-containing neurons rather than on GHRH-producing neurons (52, 53). Regardless of the direct or indirect site of action, models of lifelong actual PRL overexpression will be needed to confirm this developmental effect of hGH on PRL-regulating neurons.


   Acknowledgments
 
The authors thank Ms. Martha Romero and Ms. Rebecca Cerven for valuable technical assistance; the editorial assistance and comments on the manuscript by Dr. D. L. Hurley are appreciated. This work would not have been possible without the generosity of Drs. T. E. Wagner and J. S. Yun, who provided the transgenic males to start the breeding colony. Their help and encouragement are gratefully acknowledged.


   Footnotes
 
1 This work was supported by USPHS Grants NS-25987 (to C.J.P.) and HD-20001 (to A.B.). Back

Received March 18, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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