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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4960-4966
Copyright © 2003 by The Endocrine Society

Laminin Isoforms in Fetal and Adult Human Adrenal Cortex

Ismo Virtanen, Matti Korhonen, Noora Petäjäniemi, Tuula Karhunen, Lars-Eric Thornell, Lydia M. Sorokin and Yrjö T. Konttinen

Institute of Biomedicine/Anatomy (I.V., M.K., N.P., T.K., Y.T.K.), Haartmaninkatu 8, University of Helsinki, FIN-00014 Helsinki, Finland; Hospital for Children and Adolescents, Helsinki University Central Hospital (M.K.), Stenbäckinkatu 11, FIN-00029 Hus, Finland; Department of Experimental Pathology, University of Lund (L.M.S.), SE-22362 Lund, Sweden; Department of Integrative Medical Biology, Section for Anatomy, Umea University (L.-E.T.), SE-90187 Umea, Sweden; and Department of Medicine/Invärtes Medicin, Helsinki University Central Hospital, ORTON Research Institute and the Orthopedic Hospital of the Invalid Foundation (Y.T.K.), FIN-00280 Helsinki, Finland

Address all correspondence and requests for reprints to: Prof. Ismo Virtanen, M.D., Institute of Biomedicine/Anatomy, P.O. Box 63, Haartmaninkatu 8, University of Helsinki, FIN-00014 Helsinki, Finland. E-mail: ismo.virtanen{at}helsinki.fi.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Laminin has been proposed to influence the function of human adrenal cortex. We have studied the distribution of laminin (Ln) chains using immunofluorescence in human fetal and adult adrenal cortex. In the fetal gland Ln {alpha}2- and {alpha}5-chains were weakly expressed in the definitive zone, whereas Ln {alpha}4-, ß1-, and {gamma}1-chains occurred around vessels. In the adult gland, Ln {alpha}2-, {alpha}5-, and {gamma}1-chains were found in epithelial basement membranes (BM) in all cortical zones, Ln {alpha}4-chain in vessels, Ln ß1-chain in outer zone, and Ln ß2-chain in the two inner zones of the cortex, respectively. Among the integrins in adult gland, integrin {alpha}3-subunit was confined to basal surfaces of cortical cells, {alpha}6 to vessels, {alpha}1 to the stroma, and {alpha}2 diffusely to epithelial cells. Lutheran glycoprotein and dystroglycan occurred in the fetal gland diffusely in the definitive zone and throughout the epithelium in the adult. The isoform composition of BM of the adult adrenal gland is distinct, with Ln-2 and -10 in BM of the outer zone and Ln-4 and -11 in BM of the two inner zones. The results suggest that integrin {alpha}3ß1 and Lutheran are candidate receptors for Ln-10 and -11, whereas dystroglycan probably binds Ln-2 and -4.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ADRENAL cortex develops from mesenchymal cells attached to the lining of the coelomic cavity adjacent to the urogenital ridge. In humans, the adrenal gland develops in a process that differs from that of many other species. In the fetal adrenal gland, the cortex is divided into the definitive zone, containing mainly proliferative cells, and the fetal zone, which is largely steroidogenic, from the second trimester of gestation. During development the fetal zone involutes, leading to a decrease in the volume of the neonatal gland (1). Important recent findings were presented by Chamoux et al. (2, 3), identifying extracellular matrix (ECM) components and their integrin (Int) receptors and, further, indicating that proteins of ECM influence the development of adrenal gland, with laminin (Ln) promoting cell proliferation, fibronectin favoring cell death, and collagen type IV favoring secretion. This finding is in line with the proposal that ECM components regulate differentiation and development (4, 5). In the adult adrenal gland the cortex is typically divided into three zones: the zona glomerulosa (ZG), zona fasciculata (ZF) and zona reticularis (ZR), which undergo permanent regeneration. Cells of the adrenal gland proliferate in the external zone and subsequently migrate in a centrifetal direction, during which phenotypic transition from ZG into ZF and ZR cells occurs (6, 7).

Basement membranes (BM) are important ECM constituents of all epithelial tissues, but are also found in vessel walls and around adipose, muscle, and Schwann cells (8, 9). BM function during morphogenesis of epithelial tissues as well as in their proper maintenance and functioning in adults (9). Independent networks formed by Ln and type IV collagens and connected by nidogen-1 form the structural basis of BM (10, 11). The Ln are multifunctional proteins recognized by cells by numerous dimeric Int receptors. They form a growing protein family consisting of at least of 14 trimeric proteins and containing {alpha}-, ß-, and {gamma}-chains; at present, five {alpha}-, three ß-, and three {gamma}-chains have been described (11, 12). Different Ln isoforms show distinct localizations in various organs, such as stomach and airways (13, 14), suggesting organ- or tissue-specific functions. Immunolocalization studies have revealed a complex Ln composition in BM of many epithelial tissues. For instance, in the stomach, the glandular epithelial BM contains Ln-2 and Ln-10, whereas BM of the surface epithelium contains Ln-5 ({alpha}3ß3{gamma}2) and Ln-10 (13). In human tissues, BM of some, but not all, epithelia have been reported to also contain Ln-1 (15). In general, Ln-1 shows the most restricted distribution in epithelial BM, whereas Ln-10 is found in BM of all epithelia, and Ln-5 occurs in many, but not all, epithelial BM (11, 12, 16).

Less is known about BM and ECM compositions of human endocrine glands. In the pituitary, immunoreactivity for Ln, as revealed with a polyclonal antiserum, detecting all Ln containing the {gamma}1-chain (17), was detected in both epithelial and vascular BM and was suggested to play a role in the morphogenesis of the gland (18). In the thyroid, Ln-1 and -10 appear to be constituents of epithelial BM (15, 19), whereas in the adrenal cortex, Ln has been found in BM throughout the cortex and has been suggested to be required for homeostasis of the tissue (3, 20, 21). Falk et al. (22) reported the Ln {alpha}1-chain in several BM in the mouse adrenal gland. However, we (15) have not been able to detect Ln {alpha}1 polypeptide in either fetal or adult human adrenal gland. Similarly, Ln {alpha}1 mRNA was not detectable by in situ hybridization in the human adrenal (23); rather, an intense expression of Ln {alpha}2 mRNA was found. In a recent study, Chamoux et al. (3) showed that ECM and BM proteins coordinate specific steroidogenic pathways and cell turnover in the developing human adrenal gland.

Due to the increasing complexity of the growing Ln protein family we have used a panel of monoclonal antibodies (MAb) to detect different Ln chains and therefore several Ln isoforms in BM of fetal and adult human adrenal cortex. Our study shows that Ln-2 and Ln-10 are the Ln of epithelial BM of ZG, whereas BM of ZF and ZR contain Ln-4 and -11. Our results also show that of the Ln receptors, Int {alpha}3ß1 and Lutheran (Lu) glycoprotein are potential receptors for Ln-10 and -11, whereas dystroglycan appears to be distributed in a manner consistent with binding to Ln-2 and -4. This study reveals a noteworthy heterogeneity in BM of different zones of adrenal gland cortex and a conspicuous absence of Ln-1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue samples

Fetal (n = 8; 16–18 wk) adrenal gland tissues were obtained from spontaneous abortions caused by rupture of fetal membranes or from abortions performed because of severe maternal complications at Helsinki University Central Hospital (Helsinki, Finland) or at Jorvi Hospital (Espoo, Finland). After informed consent, 22 wk fetal specimens were obtained at the Department of Surgery, Umea University Hospital (Umea, Sweden). Adult tissue samples were obtained at extrafascial nephrectomies performed because of renal carcinomas (n = 12). The tissues were frozen in liquid nitrogen. Frozen sections were cut at 5–6 µm and fixed in acetone at -20 C. Tissue sections were stained with hematoxylin-eosin to evaluate the histology.

Indirect immunofluorescence technique

For indirect immunofluorescence of BM proteins the following MAb were used: MAb 161EB7 against Ln {alpha}1 (15), MAb 2H8 against Ln {alpha}2 (24), rat MAb 4H8-2 against Ln {alpha}2 (25), MAb BM-2 against Ln {alpha}3 (26), MAb FC10 against Ln {alpha}4 (27), MAb 4C7 against Ln {alpha}5 (28, 29), MAb PLB1 against Ln ß1 (19), MAb S5F1 against Ln ß2 (30), and MAb 113BC7 against Ln {gamma}1 (31). To detect Ln-binding Int the following MAbs were used: TS 2/7 against Int {alpha}1-subunit (32), 10G11 against Int {alpha}2-subunit (33), J143 against Int {alpha}3-subunit (32, 34), GoH3 against Int {alpha}6-subunit (35), MAb 9.1 against Int {alpha}7-subunit (36), 102DF5 against Int ß1-subunit (37), and 90BB10 against Int ß3-subunit (38). MAb BR1C221 was used to detect Ln glycoprotein (Serotec, Oxford, UK), and MAb NCL-b-DG was used to study ß-dystroglycan (Novocastra Laboratories, Newcastle Upon Tyne, UK). Bound antibodies were visualized using fluorescein isothiocyanate-coupled goat antiserum against mouse IgG (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA), tetramethylrhodamine-coupled goat antimouse IgG (Jackson ImmunoResearch Laboratories, Inc.), or fluorescein isothiocyanate-conjugated antirat antibody. The polyclonal antiserum used to detect pan-Ln staining was an antiserum against Engelbreth-Holm-Swarm-Ln (Sigma-Aldrich Corp., St. Louis, MO). After washing in PBS, the specimens were embedded in buffered glycerol and examined under a Leica Aristoplan microscope (Deerfield, IL). Control immunostainings with the conjugated antibody alone or an irrelevant primary MAb were negative.

For laser-scanning confocal microscopy, sections of adult adrenal gland were exposed to MAbs 4C7 and 4H8-2 and then exposed to Alexa Fluor 488 goat antimouse IgG and Alexa Fluor 594 goat antirat IgG (both from Molecular Probes, Eugene, OR), respectively. For laser-scanning confocal microscopy a Leica DM RXA2 fluorescence microscope and TCS SP2 confocal system were used. The fluorophores were excited with the 488- or 568-nm lines from an argon or krypton laser, respectively.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Distribution of Ln chains and Ln-binding Int and non-Int receptors in fetal human adrenal gland cortex

Immunoreactivity for Ln {alpha}2-chain was restricted to the outer capsule of the fetal adrenal gland (Fig. 1AGo). Immunoreactivity for Ln {alpha}4 was also found in the capsule, in short streaks and fibrils in the definitive zone, and in a broader fibrillar pattern in the fetal zone (Fig. 1BGo). For Ln {alpha}5-chain only a weak immunoreaction was found in the capsule (Fig. 1CGo), whereas MAbs to Ln {alpha}1- and Ln {alpha}3-chains did not react with the fetal adrenal tissue (data not shown). MAbs to Ln {gamma}1-chain (Fig. 1DGo) and ß1-chain (Fig. 1EGo) showed a broader reaction in the fetal zone and a patchy staining in the definitive zone and in the capsule, whereas MAb to Ln ß2-chain showed a more restricted staining in the capsule and in the definitive and fetal zones (Fig. 1FGo).



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  		FIG. 1. Distribution of Ln chains and receptors in human fetal adrenal gland. A, Immunoreactivity for Ln {alpha}2-chain is confined to the capsule and in a punctate pattern in the definitive zone (DZ), whereas the fetal zone (FZ) lacks immunoreactivity. B, Immunoreactivity for the Ln {alpha}4-chain is seen in fibrils extending from the capsule through the DZ and is found in more fibrillar-like deposits in the FZ. C, Ln {alpha}5-chain immunoreactivity is confined to the capsule. D, Immunoreactivity for the Ln {gamma}1-chain is located in fibrils in the FZ (arrow) similar to that for the Ln ß1-chain (E). F, The Ln ß2-chain is confined to the capsule and to isolated dots in the DZ and FZ. G, Immunoreactivity for Int {alpha}6-subunit is mainly confined to the capsule and some cells in the FZ. H, Immunoreactivity for Lu antigen is confined to the capsule, whereas that of ß-dystroglycan (arrows in I) is found in dots and fibrils in the DZ. Magnification, x400.

 
As localization of some of the Int subunits has recently been reported in fetal human adrenal gland (2) and our results on fetal specimens agreed with these results, we concentrated on adult human specimens and only show fetal data on Ln receptors that were not reported in the aforementioned study. In the fetal adrenal cortex Int {alpha}6-subunit was found only in the capsule and in some blood vessels (Fig. 1GGo) with a pattern similar to that seen with anti-Lu blood group antigen (Fig. 1HGo), whereas a punctate immunoreactivity for dystroglycan was found in the definitive zone and, to a lesser extent, also in the fetal zone (Fig. 1IGo).

Distribution of Ln chains and Ln-binding Int and non-Int receptors in developing and adult human adrenal gland cortex

In the adult adrenal gland an intense BM-confined immunoreactivity for Ln {alpha}2-chain was detected around glandular structures throughout the cortex (Fig. 2AGo). Also BM of chromaffin cells in the medulla were intensively labeled (data not shown). A similar BM immunoreactivity was found for Ln {alpha}5-chain, plus an intense reactivity with blood vessel walls (Fig. 2BGo). No immunolabeling was detected for Ln {alpha}1- or {alpha}3-chains (data not shown). MAb FC10 against Ln {alpha}4-chain gave a strong immunoreaction in the capsule and BM of blood vessels (Fig. 2CGo). Immunoreactivity for Ln {gamma}1-chain was found in the capsule and in all cortical BM (Fig. 2DGo). A distinct BM-confined reciprocal labeling was obtained with MAbs against Ln ß1-chain (Fig. 2EGo) and ß2-chain (Fig. 2FGo); Ln ß1-chain was found only in BM of ZG, whereas Ln ß2-chain was located in BM of ZF and ZR. No immunoreactivity was found with MAbs against Ln ß3- or {gamma}2-chains (not shown). The differential distribution of Ln {alpha}2- and Ln {alpha}5-chains was studied more carefully in double-stained sections using laser scanning confocal microscopy. Both Ln {alpha}2- and {alpha}5-chains (Fig. 3Go) were localized in epithelial BM, as demonstrated in the merged image in Fig. 3Go, whereas only the {alpha}5-chain was also found in vessel walls.



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  		FIG. 2. Distribution of Ln chains in adult human adrenal gland. A, A continuous linear BM-like distribution is found for Ln {alpha}2-chain throughout the whole cortex and more diffusely in the capsule. B, A broader and continuous distribution was found for Ln {alpha}5-chain throughout the cortex in epithelial and vessel BM. C, The Ln {alpha}4-chain localized in vessel walls (arrows) between glandular elements. D, The Ln {gamma}1-chain showed a continuous linear immunoreactivity throughout the whole cortical region. E, Immunoreactivity for the Ln ß1-chain was restricted to the ZG part of the cortex only, with scattered punctate and variable fibrillar reactivity in the lower zones. F, Ln ß2-chain immunoreactivity was clearly lacking in the ZG, whereas a linear reaction was found in ZF and ZR. Magnification, x300.

 


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  		FIG. 3. Laser scanning confocal microscopy of human adult adrenal gland for Ln {alpha}2- and Ln {alpha}5-chains. Immunoreactivities for Ln {alpha}2-chain (red) and Ln {alpha}5-chain (green) are colocalized in glandular BM, as shown in the merged confocal image. The vessel walls contain only Ln {alpha}5-chain. Magnification, x300.

 
Immunoreactivity for Int {alpha}1-subunit disclosed diffuse, stromal and capsular localization (Fig. 4AGo), whereas that for Int {alpha}2-subunit showed diffuse, but restricted, localization on glandular cells in ZG (Fig. 4BGo). In contrast, MAb to Int {alpha}3-subunit revealed a basally confined distribution in the epithelial cells throughout the cortex (Fig. 4CGo). Immunoreactivity for Int {alpha}6-subunit was detected only in vessel walls (Fig. 4DGo). No immunoreactivity for Int {alpha}7-subunit was detected in adult or fetal specimens (not shown). Immunoreactivity for Int ß3-subunit was seen only in dot-like bright structures, compatible with reactivity with platelets and white blood cells (not shown). Immunoreactivity for the Lu blood group antigen was detected in a strictly polarized manner on epithelial cells (Fig. 4EGo), and that for dystroglycan was also found throughout the cortex on the cells in a polarized manner (Fig. 4FGo).



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  		FIG. 4. Distribution of Int and non-Int Ln receptors in adult human adrenal gland. A, Immunoreactivity for Int {alpha}1-subunit is seen diffusely outside the glandular cells in the stromal region and in the capsule. B, Immunoreactivity for Int {alpha}2-subunit is seen diffusely in the glandular cells, especially in the ZG. C, Int {alpha}3-subunit is found in a polarized manner in all cortical glandular cells and in the capsule. D, Int {alpha}6-subunit is only located to vessel walls (arrow) in the cortex and in the capsule. E, Lu antigen is distributed in a polarized manner in glandular cells and in the capsule. F, ß-Dystroglycan immunoreactivity is found in a polarized manner in cortical glandular cells. Magnification, x300.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present study show that BM organization found in the adult adrenal cortex is acquired rather late during development, as no distinctive organization could be found in the fetal adrenal gland with the exception of the vessel walls.

The results on fetal adrenal gland showed that in the definitive zone of 16–22 wk specimens, Ln {alpha}2- and {alpha}5-chains were only sparsely found in the capsule and as short strands extending to the definitive zone. This is in accordance with the results reported by Chamoux et al. (2), who reported a weak Ln immunoreactivity, detected with a polyclonal rabbit antiserum to mouse Ln-1. A much broader distribution that included the vasculature was apparent for Ln {alpha}4-, ß1-, and {gamma}1-chains in the fetal zone.

By using chain-specific MAb against different Ln chains we could show a distinctive distribution of Ln in the BM of adult adrenal cortex. The results show that Ln {alpha}5- and {alpha}2-chains, the latter a typical mesenchymal Ln (11), are the major Ln {alpha}-chains in epithelial BM throughout the cortex. Ln {alpha}5-chain was also located in BM of vessel walls. In contrast, another Ln chain of mesenchymal origin (11), Ln {alpha}4, was found only in the capsule and in vessel walls. A distinctive finding was that Ln ß1- and ß2-chains showed a reciprocal distribution in the cortex, indicating that Ln-2 and -10 occur in BM of ZG, and Ln-4 and -11 occur in BM of ZF and ZR. Although the adrenal cortex is traditionally seen as divided into three morphological zones, the functional significance of such a separation has remained elusive. It is known that the ZG is responsible for aldosterone production and is differently controlled to ZF and ZR, which synthesize glucocorticoids and sex hormones, respectively (6, 39, 40). This study shows for the first time that the ZG also differs from ZF and ZR in its cytostructural BM properties. Although the functional implications of these findings remain to be established, it is notable that Ln-11 has to date been identified only in distinct sites, such as the glomerular BM of the kidney and BM of the neuromuscular synaptic cleft in skeletal muscle (41).

There are few studies that have attempted to elucidate the role of ECM molecules such as Ln in the production of steroid hormones in endocrine glands. Diaz et al. (42) recently showed that ECM proteins can modulate steroidogenesis of Leydig cells in culture, but they did not find any effect with mouse Ln-1. However, mouse Ln-1 was found to suppress progesterone production in human luteinizing granulosa cells through interaction with Int {alpha}6ß1 (43). Similarly, in the adrenal gland, mouse Ln-1 has been found to modulate steroid production (21, 44). On the other hand, Chamoux et al. (3) have shown that different ECM proteins differentially modulate cell behavior during development of the human adrenal gland, with Ln favoring cell proliferation, fibronectin favoring cell death, and collagen type IV favoring secretion, respectively. In all of these studies mouse Ln-1 extracted from Engelbreth-Holm-Swarm sarcoma was used, which we have shown, both here and in previous studies (15), does not occur in the human adrenal gland. As different Ln interact with distinct Int or non-Int cellular receptors and thereby elicit different functional signals (11, 12), it is clear that studies of the role of Ln in steroidogenic glands should focus on the biologically relevant Ln isoforms.

Our results on Int and non-Int receptors for Ln suggest that the Int {alpha}3ß1 complex is probably a receptor for Ln-10 and -11 in the adult adrenal gland, which is compatible with in vitro data (45, 46, 47). In addition, the distribution of the Lu glycoprotein, a recently reported non-Int receptor for Ln-10/11 (48, 49) in adult tissue is also consistent with it being a receptor for Ln-10/11. However, Int {alpha}vß3, a recently suggested receptor for Ln containing the {alpha}5-chain (50), did not show a distinctive epithelial distribution in the adrenal cortex.

The Int receptor for Ln-2 is less well defined, but a major candidate Int {alpha}7ß1 (51), was not found in fetal or adult adrenal cortex, while other potential receptors, such as Int {alpha}1ß1 and {alpha}2ß1 (52), were not present in adult gland in a distribution compatible with a receptor function. A non-Int receptor for Ln-2, dystroglycan (53), showed a punctate distribution throughout DZ of fetal adrenal cortex and in the adult gland a linear polarized distribution compatible with the suggestions that it would be a BM receptor for Ln-2 and -4. The presence of dystroglycan in DZ before any Ln chains is also compatible with the hypothesis that it could initiate BM assembly (54). These findings, together with the obvious lack of Ln and their Int receptors in the fetal zone of developing adrenal gland, suggest that Ln do not play a major role in the steroidogenesis of the fetal gland, in line with the results of Chamoux et al. (2).

Our results show that the BM composition of the human adult adrenal gland is very distinctive, consisting of Ln-2, -4, -10 and -11 and undergoing dramatic developmental changes. The results also show that changes in BM composition are accompanied by corresponding changes in the expression of their receptors.


   Acknowledgments
 
The skillful technical assistance of Ms. Pipsa Kaipainen, Mr. Hannu Kamppinen, Mr. Reijo Karppinen, Ms. Marja-Leena Piironen, and Ms. Outi Rauanheimo is kindly acknowledged. Professors E. Engvall, M. E. Hemler, R. H. Kramer, L. J. Old, and U. M. Wewer are acknowledged for providing MAbs.


   Footnotes
 
This work was supported by clinical EVO research grants (TYH 0056, TYH 0215, TYH 0341, and TYH 8307), an Invalid Foundation 9750/2 grant, Finska Läkaresällskapet, the Academy of Finland, Center for Technological Advancement, Ministry of Education, and University of Helsinki Group of Excellence scheme.

Abbreviations: BM, Basement membrane; ECM, extracellular matrix; Int, integrin; Ln, laminin; Lu, Lutheran; MAb, monoclonal antibodies; ZF, zona fasciculata; ZG, zona glomerulosa; ZR, zona reticularis.

Received March 10, 2003.

Accepted June 14, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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