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Departments of Medicine (G.N.H., T.L., M.G., R.C.F., S.M., A.C.K., L.C.), Physiology (G.N.H., S.M.), Human Genetics (G.N.H., A.C.K.), Biochemistry (M.L.T.), and McGill Cancer Centre (M.L.T.), McGill University and Calcium Research Laboratory (G.N.H., L.C.), and Hormones and Cancer Research Unit (G.N.H.), Royal Victoria Hospital, Montreal, Québec, Canada H3A 1A1; and Département de Pharmacologie (R.De., R.Da.), Faculté de Médicine et Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada J1H 5N5
Address all correspondence and requests for reprints to: Dr. Geoffrey N. Hendy, Calcium Research Laboratory, Royal Victoria Hospital, 687 Pine Avenue West, Room H4.67, Montreal, Québec, Canada H3A 1A1. E-mail: geoffrey.hendy{at}mcgill.ca.
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The ubiquitous presence of granins in neuroendocrine cells suggests they play important roles in regulated secretory function. It has been proposed that intracellularly, granins play a role in secretory granule formation and targeting of peptide hormones and neurotransmitters to granules of the regulated secretory pathway by virtue of their ability to aggregate in the low-pH, high-calcium environment of the trans-Golgi network (reviewed in Ref. 7). Outside the cell, granin-derived peptides have been proposed to function as modulators of neuroendocrine cell secretory activity, for example, as well as to have other biological activities (reviewed in Refs.7 and 8).
A characteristic of CgA is its neuroendocrine specific pattern of expression, which is associated with the proximal promoter of the Chga gene (9, 10). The distribution of CgA, which is much more widespread than any peptide hormone, has made the measurement of plasma CgA a more widely applicable tool in the diagnosis of neuroendocrine neoplasms. In addition, CgA immunohistochemistry can establish the neuroendocrine nature of tumors, and this can have implications for treatment (reviewed in Ref. 5).
The human CHGA gene locus at chromosome 14q32 (8, 11, 12) has not been linked to any inherited disease. In mouse the Chga gene is on chromosome 12 (13) in a region that is not involved in any known mouse mutant strain. The Chga gene is on rat chromosome 6. Although releasable CgA from both adrenal and sympathetic neuronal pools is augmented in essential (hereditary) hypertension, the study of natural rodent models of hypertension such as the spontaneously hypertensive rat show that the Chga locus is not directly linked to the blood pressure elevation (14).
Studies that report on the many potential functions of CgA have been based almost exclusively upon in vitro cell culture experiments. To provide insights into the roles played by CgA in the whole animal, mouse models in which the Chga gene is disrupted or its expression reduced are being developed. A recent study focused on the role of CgA in modulating catecholamine release and changes in cardiovascular function (15). The increased blood pressure of mice deleted for the Chga gene was normalized when this animal was crossed with a transgenic mouse expressing the human CHGA gene. Another study, which used a transgenic Chga antisense approach, focused exclusively on the potential role of CgA in adrenal chromaffin granulogenesis (16). Some differences between the two studies could be noted with respect to the viability of mice and whether adrenal medullary dense-core granules increased or decreased in size in association with reduction of Chga gene expression.
In the present study, we report a novel mouse model null for the Chga gene. These mice are viable and fertile and have no obvious developmental abnormalities. Although locomotor and endocrine functions appear grossly unimpaired, urinary catecholamine excretion is elevated in the Chga null mutant mice. Their adrenal glands are structurally unremarkable, and vesicle size and number of chromaffin cells are normal. However, the expression levels of other granins are up-regulated in adrenal medulla and other endocrine glands, suggesting that this biochemical phenotype likely compensates for the Chga deficiency.
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RESULTS |
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was used to inactivate one allele of the Chga gene in embryonic stem (ES) cells. The inactivated allele lacked exon I to exon IV. Two independent ES cell clones (Fig. 1B) were used to generate two lines of mice heterozygous for the mutation, each of which was then interbred to generate Chga null (–/–) mice (Fig. 1C). Litter sizes were no different from normal, and the mutated allele was transmitted to the progeny with the expected Mendelian frequency (Table 1). Thus, haploinsufficiency of Chga did not affect embryonic survival. By Northern blot analysis, adrenal expression of the CgA mRNA in (+/–) mice was reduced relative to that in (+/+) mice, and, in (–/–) mice it was undetectable (Fig. 1D). This was observed with both cDNA probes used, one for exons I–IV (the portion deleted in the targeted allele) and one for exons V–VIII. Thus, the targeting strategy had successfully ablated the normal Chga mRNA, and there was no evidence of a read-through transcript derived from Chga exons V–VIII that remained in the targeted allele.
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). To test whether the Chga gene ablation strategy had any impact upon the expression of the flanking genes, an RT-PCR analysis of Golga5 and Itpk1 transcripts of wild-type (–/–), and heterozygous (+/–) and homozygous (–/–) mice was made (Fig. 2B). Adrenal gland mRNA levels of Golga5 and Itpk1 were completely normal in the heterozygous and homozygous Chga null mutant mice (Fig. 2C), indicating that the Chga ablation strategy had not affected expression of the neighboring genes.
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). The null mutant mice were no different from wild-type with respect to gross behavior, locomotor activity, and reproductive ability. Matings of Chga (–/–) mice produced litters of normal size, and the offspring were normal. Thus, there was no evidence of markedly altered secretory function of the sympathetic nervous system, pituitary somatotrophs, or gonadotrophs.
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). Normal hepatic function of Chga null (–/–) and heterozygous (+/–) mutant mice was indicated by serum levels of liver enzymes and other metabolic products the same as in wild-type (–/–) mice. Unimpaired renal function was indicated by the normal serum creatinine, urea, and electrolyte levels in the mutant mice. Unimpaired endocrine gland function was indicated by the normal serum levels of glucose (pancreatic islets of Langerhans) and calcium and phosphorus (parathyroid glands and thyroid C cells) in the mutant mice. Mean serum PTH levels were not different among groups being 47.7 ± 17 pg/ml (mean ± SE) (+/+), 41.8 ± 15 pg/ml (+/–), and 39.8 ± 17 pg/ml (–/–) (n = 8–10).
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, panels A and B). The complete absence of the CgA protein in the Chga (–/–) mice was confirmed by the lack of immunostaining for CgA compared with the abundant signal in the adrenal medulla of Chga (+/+) mice (data not shown).
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and 7). The average granule size (measured as granule area) was not significantly different in wild-type and Chga (–/–) mice [epinephrine-type: (+/+), 0.0159 ± 0.007 µm2 (mean ± SE), (–/–), 0.0165 ± 0.011; norepinephrine-type, (+/+), 0.018 ± 0.009, (–/–), 0.0171 ± 0.006].
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). In contrast, mRNA levels of the related granins, CgB, SgI, SgII, SgIII, SgV, and SgVI, were up-regulated approximately 2- and 3-fold, in (+/–) and (–/–) mice, respectively, relative to wild-type levels (Fig. 8). Also, adrenal medullary tyrosine hydroxylase mRNA was increased in the (–/–) mice being approximately 2-fold that of wild-type.
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). It was confirmed at the protein level for the granins, CgB and SgIII, that there was marked up-regulation, approximately 3- and 4-fold in the (+/–) and (–/–) mice, respectively, relative to wild type.
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). In addition, marked up-regulation of related granin mRNAs, either CgB in hypothalamus, or SgII in pituitary and thyroid, occurred in the Chga null mutant mice (Fig. 10).
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and Table 3).
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DISCUSSION |
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The genes flanking Chga are Golga5 and Itpk1. Golga5 encodes a member of the golgin family of proteins that localize to the Golgi. The protein is a coiled-coil membrane protein that has been postulated to play a role in vesicle tethering and docking (17, 18). The protein is widely expressed in both endocrine and nonendocrine cells. Itpk1 encodes inositol 1,3,4-trisphosphate 5/6 kinase that is one of a series of inositol phosphate kinases that modify inositol 1,4,5-trisphosphate (which is generated by activated phospholipase C). Itpk1 also exhibits protein kinase activity and associates with the so-called COP9 signalosome that regulates ubiquitin ligases (19). The Itpk1 protein is widely expressed in both endocrine and nonendocrine cells. Disruption of the Csn2 gene encoding one of the components of the COP9 signalosome causes early embryonic death in mice (20). We found that Golga5 and Itpk1 transcript levels were normal in the heterozygous and homozygous Chga null mutant mice, providing reassurance that our Chga ablation strategy had not impacted upon the expression of these neighboring genes.
Previous studies have implicated CgA in granulogenesis as one of a number of secretory granule cargo proteins that aggregate and form the foci for the budding off of vesicles in the trans-Golgi network, which then become mature dense-core granules. More recently, the debate has shifted to the idea of CgA as a specific on/off switch controlling dense-core secretory granule biogenesis in endocrine cells. In one study, down-regulation of CgA in some clones of the neuroendocrine cell line, PC12, achieved by stable expression of antisense CgA RNA, was associated with loss of dense-core secretory granules (21). In the selected clones, there was impairment of regulated secretion and reduction of other secretory granule proteins such as CgB. It was suggested that overexpression of CgA in nonendocrine cells could induce dense-core granules. These authors did not find evidence that CgB functioned in a similar fashion to CgA. However, another group has reported that, in their hands, reduction of CgB in neuroendocrine cell lines led to a reduction in dense-core granules (22). This group and one other found that overexpression of CgB in nonendocrine cells resulted in structures having the appearance of dense-core granules (22, 23). Most recently, a reinvestigation of the relationship between CgA and dense-core granules using many clones of the neuroendocrine PC-12 cell line failed to confirm the existence of a CgA-dependent, on/off control switch (24). Rather, it was demonstrated that the composition of dense-core granules can be remarkably heterogeneous with respect to the relative amounts of each granin found. Furthermore, it was suggested that the structures induced in nonsecretory cells by exogenous CgA expression were not proper dense-core granules but were more likely to be of a lysosomal nature. Therefore, some of the conclusions made about the role of granins (and specifically CgA) in secretory cell granulogenesis derived from in vitro studies of cell lines should be viewed cautiously (25).
In two recent reports, the role of CgA in vivo in adrenal chromaffin granulogenesis was examined. Whereas the study in which the Chga gene was deleted found a decrease in both chromaffin granule number and size (15), the study in which CgA expression was reduced by a transgenic antisense technique reported a decrease in chromaffin granule number but an increase in size (16). In neither of these studies were the epinephrine and norepinephrine granules analyzed separately. There are two types of chromaffin cells: those producing and storing norepinephrine and those producing and storing epinephrine (26). Norepinephrine granules are larger, electron opaque, with a prominent halo between granule membrane and dense core (which is often excentric); epinephrine granules are smaller, finely granular, filling the enclosing membrane and with no halo (http://pathologyoutlines.com/adrenal.html). It would be extremely hazardous to base conclusions with respect to granule size and number after examining sections of adrenal medulla at random without separately analyzing the two types of cells and granules. In the present investigation, we did not find any significant differences in chromaffin granule number and size (epinephrine and norepinephrine types analyzed separately) between wild-type mice and Chga knockout mice.
In the present study, in the whole animal, it was noted that the expression levels of the other granins were increased in both the Chga (+/–) and Chga (–/–) mice relative to wild type. This was documented for mRNA expression in adrenal medulla, hypothalamus, pituitary, and thyroid, and additionally for granin protein levels in the adrenal medulla. Thus, our data do not support the idea of a particular granin functioning as a dense-core granule on/off switch. Rather, the compensatory increases in the other granins that occur when CgA is depleted would support the notion of granins collectively being critical for granule formation. Thus, to some extent, one granin can substitute for the loss of another. The compensatory increase in granin expression is clearly very important, but the mechanism remains to be determined.
CgA has been proposed to be a precursor for multiple biologically active peptides that act as autocrine or paracrine inhibitors of secretion. Some examples are: pancreastatin, which inhibits glucose-stimulated insulin release from the perfused rat pancreas (27); parastatin, which inhibits PTH release from parathyroid cells in culture (28); and catestatin, which antagonizes nicotinic-cholinergic stimulation of catecholamine secretion (29). It is thought that these effects are mediated by specific cell-surface receptors, although with the exception of the noncompetitive inhibition of the nicotinic acetylcholine receptor by catestatin in chromaffin cells, such receptors have not been identified. In the present study, Chga null mutant mice were of normal weight at birth and grew at the normal rate. The null mutant mice were no different than wild type with respect to locomotor activity and reproductive ability. Thus, there was no evidence of altered secretory function of pituitary somatotrophs or gonadotrophs. The serum biochemical profiles of Chga (–/–) mice were no different than wild type. Unimpaired endocrine gland function was indicated by the normal serum levels of glucose (pancreatic islets of Langerhans) and calcium and phosphorus (parathyroid glands and thyroid C cells). Baseline serum PTH levels were not abnormal in the Chga null mutant mice described here. However, higher urinary catecholamine excretion was noted indicative of a specific effect of CgA on adrenal chromaffin cell and/or sympathetic neuron function.
The phenotype of the recently described mouse model in which the Chga gene was inactivated (15) differs in some respects from that of the model described here. In these mice, the null allele was not inherited in a Mendelian fashion but rather there was a high level of unexplained prenatal lethality (homozygous null, 73%; heterozygous null, 22%). For the mice that were viable, decreases in chromaffin granule size and number were reported. Differences between the phenotype (and its heterogeneity) of the Chga (–/–) mice generated in that study and the present report may relate to different mouse genetic backgrounds, but this remains to be determined.
In summary, we have generated a mouse strain deleted for the Chga gene. The mice demonstrate a striking biochemical phenotype in that expression of other granins is markedly up-regulated in endocrine tissues such as the adrenal medulla. This would support the notion of granins collectively being important for neural and endocrine function, and that a decrease in the level of one type of granin can be compensated for by increased expression of the other granins.
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MATERIALS AND METHODS |
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A second 
-phage genomic clone was digested with EcoRI yielding a 5.0-kb fragment, spanning Chga exons IV–VII, that was cloned into pBluescript II SK. From this, the 3.0-kb XbaI-BamHI fragment containing exons V and VI was ligated into the pNT vector that already contained the 5'-flanking portion of the Chga gene. This placed the Chga exons V and VI fragment in the same orientation as, and downstream of, the neomycin resistance gene cassette in the pNT vector. This completed the construction of the targeting vector (Fig. 1A
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Transfection of ES Cells and Generation of Chga-Deficient Mice
ES RI cells were seeded onto a mitomycin C (Sigma Chemical Co., St. Louis, MO)-inactivated feeder layer in DMEM (Life Technologies, Inc., Baltimore, MD), containing 1000 U/ml leukemia inhibitory factor (Life Technologies, Inc., Gaithersburg, MD) and 15% fetal calf serum (Hyclone Laboratories, Inc., Logan, UT) as previously described (30). After trypsinization, 107 ES RI cells were suspended in 1 ml PBS and mixed with NotI-linearized targeting vector DNA at a concentration of 50 µg/ml. Electroporation was performed using a Gene Pulser (Bio-Rad Laboratories, Mississauga, Ontario, Canada) at 500 µF capacitance and 240 mV. Transfected clones were selected in either one of two ways; 1) selection with both neomycin (G418, 300 µg/ml) and 2 µM Gancycline; or 2) neomycin (G418, 400 µg/ml) only. In each case, clones that had undergone homologous recombination were identified by Southern blot analysis.
Two independent ES cell clones were injected into 3.5-d BALB/c mouse blastocysts, which were then reimplanted into pseudopregnant CD1 mice. Chimeric male offspring were backcrossed with BALB/c females, and germline transmission was obtained. Chga null (–/–) mice were generated by intercrossing F1 heterozygous mice and showed a similar phenotype irrespective of their ES cell clone of origin.
All animal experiments were carried out in compliance with and approval by the Institutional Animal Care and Use Committee. Mice for generation of chimeras were from Charles River Laboratories, Inc. (St. Constant, Montreal, Quebec, Canada).
Southern Blot and PCR Analysis of ES Cell and Mouse Tail DNA
For Southern blot analysis, ES cell DNA was digested with either a BamHI/KpnI combination, SphI or XhoI, and after gel electrophoresis, the blots were hybridized with either a 32P-labeled BamHI-XhoI 5'-flanking region probe (BamHI/KpnI digests) or a 32P-labeled exon VII probe (SphI and XhoI digests) indicated in Fig. 1A. After autoradiography the blots were stripped and reprobed with a 32P-labeled neomycin gene probe. For analysis of mouse tail DNA, a multiplex PCR was used with a forward primer within exon III, 5'-GATGAAGTGCGTCCTGGAAGTCATCTCCGA-3', and a reverse primer within exon IV, 5'-CTTGGAGAGCCAGGTCTTGAAGTTCCTTCA-3' (which amplifies part of the Chga gene that is deleted in the mutant allele), and a forward primer NeoF 5'-ACAACAGACAATCGGCTGCTC-3' and reverse primer NeoR 5'-CCATGGGTCACGACGAGATC-3' (which amplifies the neomycin resistance gene in the mutant allele). The conditions were 30 cycles of denaturation, 94 C, 1 min; annealing, 58 C, 1 min, and extension, 72 C, 1 min.
RT-PCR
Total RNA was extracted from pairs of adrenal glands of 8- to 12-wk-old male mice using Trizol (Invitrogen, San Diego, CA). First-strand cDNA was made by reverse transcribing DNAse-I-treated total RNA with recombinant superscript II RNase H using oligo(dT)15–18 as described previously (31). Portions of the Golga5, Chga, Itpk1, and ß-actin cDNAs were amplified with the following primer sets: Golga5 (forward), 5'-CAGTTCGGATTCTGTGTGCCTGAAGT-3'; reverse, 5'-GAGTATCCGTGTAGCTTTCTGCTTGTA-3': Chga (forward), 5'-GGCCCAGCAGCCGCTGAAGCAGCA-3'; reverse; 5'-CTCTGCGGTTGGCGCTGCCCTCCTC-3': Itpk1 (forward), 5'-CAGAATCTGCTCGCCGCCTTTCATG-3'; reverse; 5'-AAGGCATTGACATCGATGACTGCA-3': ß-actin (forward), 5'-ATGGATGACGATATCGCTGCGCTC-3'; Reverse, 5'-CGTAGATGGGCACAGTGTGGGTGA-3'. The PCR mixture, Taq polymerase, and PCR amplification conditions were as described previously (31), and the cycle number was 30, except for ß-actin (24 cycles). Aliquots (10 µl) of the PCRs were electrophoresed through ethidium bromide-stained 1% agarose gels.
Northern Blot Analysis
Total RNA was extracted from pooled adrenals of 8- to 12-wk-old male mice, and 20-µg aliquots were subjected to Northern blot analysis with 32P-labeled probes.
Western Blot Analysis
Pooled adrenal glands from 8- to 12-wk-old male mice were lysed, and 10-µg aliquots of the lysates were subjected to Western blot analysis as described previously (10). Antibodies used were against CgA, CgB, and SgIII. Antibody-antigen complexes were detected by chemiluminescence using the Lumi-Light kit (Roche Applied Sciences, Indianapolis, IN).
Biochemical and Hormonal Analyses
Blood samples were obtained by retroorbital phlebotomy from 8- to 12-wk-old mice that had been fasted overnight, and serum biochemistries were determined by autoanalyzer. Serum intact PTH was determined by a two-site immunoradiometric assay (Immutopics, San Clemente, CA).
Histological Analysis
Chga (+/+) and Chga (–/–) mice (12 wk of age) were killed by cervical dislocation, and adrenals were removed and fixed in 10% buffered formalin and embedded in paraffin, and 5-µm sections were stained with hematoxylin and eosin. For immunohistochemistry, adrenals were fixed in 4% paraformaldehyde and embedded in paraffin, and 5 µm sections were incubated overnight with a 1:200 dilution of a polyclonal antibody raised against intact CgA (DiaSorin, Inc., Stillwater, MN). Staining was done with the Biotin Streptavidin/horseradish peroxidase method.
For electron microscopy, 12-wk-old mice [Chga (+/+) and Chga (–/–)] were anesthetized with nembutal and perfused through the left ventricle with 4% paraformaldehyde diluted in 0.1 M phosphate buffer (pH 7.4). The adrenals were extracted and immersed in the same fixative for 6 h at 4 C. Cryostat sections (8 µm) were collected on poly L-lysine-coated glass slides. After fixing with osmium tetroxide for 2–3 h, sections were dehydrated with increasing concentrations of acetone and embedded in Polybed 812 (Polyscience, Inc., Warrington, PA). Thin sections were observed under transmission electron microscopy (JEM-1001CXII, Jeol, Tokyo, Japan). Cells were photographed at x4000 magnification, and the analysis of granule morphology was done blind to the genotype of the animal (32). Approximately 20 cells per mouse were photographed, and granule area and number were measured using the public domain NIH Image 1.61.2 program (developed at the National Institutes of Health, Bethesda, MD). For granule area, a field between the nucleus and plasma membrane was magnified, and approximately 10 granules per cell were randomly measured working from top left to right (wild-type, 160 granules from 15 micrographs from five mice; Chga (–/–), 160 granules from 15 micrographs from five mice). Granule number was estimated by counting the number (in the adrenal medulla) in a measured area between the nucleus and plasma membrane or (in the pituitary) per cell (10–15 cells from five wild-type mice; 10–15 cells from 5 Chga (–/–) mice). Mean values from the different genotypes were compared by Student’s t test, and a P value of less than 0.05 was taken as being significant.
Measurement of Urinary Catecholamines
Mice (8–12 wk old) were placed individually in metabolic cages for 3 d to acclimatize, and then urine was collected over the next 24 h. Urine pH was maintained at less than 3 with HCl, urine volume was measured, and aliquots were frozen at –80 C. Urine catecholamines were measured by HPLC (33).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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G.N.H, T.L., M.G., R.C.F., S.M., R.De., R.Da., A.C.K., M.L.T., and L.C. have nothing to declare.
First Published Online March 23, 2006
Abbreviations: CgA, Chromogranin A; ES, embryonic stem; SgII, secretogranin II.
Received for publication September 29, 2005. Accepted for publication March 13, 2006.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1.5). 
, Chga (+/+); 
, Chga (–/–).
