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Endocrinology Vol. 145, No. 10 4775-4780
Copyright © 2004 by The Endocrine Society

The Steroidogenic Acute Regulatory Protein Is Expressed in Steroidogenic Cells of the Day-Old Brain

Steven R. King, Stephen D. Ginsberg, Tomohiro Ishii, Roy G. Smith, Keith L. Parker and Dolores J. Lamb

Scott Department of Urology (S.R.K., D.J.L.), Huffington Center on Aging (R.G.S.), Molecular and Cellular Biology (R.G.S., D.J.L.), Baylor College of Medicine, Houston, Texas 77030; Center for Dementia Research, Nathan Kline Institute, and Departments of Psychiatry, Physiology & Neuroscience, New York University School of Medicine (S.D.G.), Orangeburg, New York 10962; and Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center (T.I., K.L.P.), Dallas, Texas 75390

Address all correspondence and requests for reprints to: Dr. Steven R. King, Room N730, Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3498. E-mail: srking{at}bcm.tmc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although recent research has focused on the fundamental role(s) of steroids synthesized de novo in the brain on development, the mechanism by which production of these neurosteroids is regulated remains unclear. Steroid production in peripheral tissues is acutely regulated by the steroidogenic acute regulatory (StAR) protein, which mediates the rate-limiting step in steroid biosynthesis: the intramitochondrial delivery of cholesterol to cytochrome P450scc for conversion to steroid. We recently demonstrated that StAR is present in discrete cell types in the adult brain, suggesting that neurosteroid production is mediated by StAR. Nevertheless, little is known regarding the presence of StAR in the developing brain. In the present study, the presence of StAR and for the first time, its homolog, the putative cholesterol transport protein metastatic lymph node 64 (MLN64), were defined in the neonatal mouse brain using immunocytochemical techniques. Both StAR and MLN64 were found to be present in the brain with staining patterns characteristic to each protein, indicating the authenticity of StAR and MLN64 immunoreactivity. Furthermore, we found MLN64 to be expressed in the adult brain as well, apparently at higher levels than StAR. Importantly, StAR protein is present in cells that also express P450scc. These data suggest that, as with the adult, neurosteroid production during development occurs through a StAR-mediated pathway.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THERE IS INCREASING evidence that steroids are synthesized de novo in the brain at physiologically significant levels (Refs. 1 and 2 ; and reviewed in Refs. 3, 4, 5). These compounds, called neurosteroids, are thought to serve important roles in neuroprotection, modulation of certain brain functions, and neuronal development. Thus, understanding the role of neurosteroids in the central nervous system (CNS) potentially has significant clinical and therapeutic implications. Nevertheless, how neurosteroid production is regulated remains unclear. The regulated step in steroidogenesis is the delivery of cholesterol from the outer to the inner mitochondrial membrane, where cytochrome P450scc converts it to the first steroid formed, pregnenolone. This step is mediated in peripheral tissues by the steroidogenic acute regulatory (StAR) protein (Ref. 6 ; and reviewed in Ref. 7). StAR is present in all tissues in which steroid synthesis is acutely regulated. Mutations in StAR result in congenital lipoid adrenal hyperplasia, a condition in which patients have a profound deficit in steroid production and can die from adrenal steroid insufficiency (8, 9, 10). When the StAR gene is knocked out in mice, these animals present a similar, lethal pathology (11, 12). There is only one described homolog to StAR with significant sequence identity, metastatic lymph node 64 (MLN64) protein (13, 14). First identified in malignant breast tumors, MLN64 is an integral membrane protein in late endosomes that may also be involved in cholesterol trafficking and has been proposed to be directly involved in steroidogenesis (13, 14, 15, 16).

Although neurosteroids are produced during development and may play an important role in neuronal maturation, little information exists to show that StAR or MLN64 proteins are present and developmentally regulated in the CNS. Whereas cytochrome P450scc is developmentally expressed in the rat CNS (17), the presence of this enzyme is only indicative of the capability of cells to produce steroid. The coexpression of StAR would distinguish cells actively engaged in neurosteroid synthesis (18). We previously demonstrated that StAR is produced in various regions of the adult brain in mouse and human and that its expression colocalized to cells that also express P450scc (steroidogenic cells) (19). However, it remains unknown whether StAR expression is confined to steroidogenic cell types. The presence of StAR was reported in the developing rat brain (19, 20). In the present report, we examined the expression of StAR at the P1 developmental stage in mouse brain to characterize whether neurosteroid synthesis could be mediated by StAR action during development and whether StAR is expressed in developing steroidogenic cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Antisera
Three anti-StAR antisera were used: an antipeptide antisera against amino acids (aa) 88–98 of mouse StAR generously provided by Dr. Douglas M. Stocco (Texas Tech University Health Sciences Center, Lubbock, TX) (17), a second derived against recombinant mouse StAR protein (a generous gift from Dr. Dale Buchanan Hales, University of Illinois, Chicago, IL) (21), and a third against rat StAR (Affinity Bioreagents, Golden, CO). Monoclonal antisera against aa369–384 and polyclonal antisera against aa1–19 of human MLN64 were kindly provided by Dr. Catherine Tomasetto (Institut National de la Santé et de la Recherche Médicale, Illkirch, France) (14, 15). Polyclonal antisera against rat MLN64 was obtained from Affinity Bioreagents. Antisera directed against aa421–441 in rat P450scc was obtained from Chemicon International (Temecula, CA). This antisera was previously found to recognize P450scc with high specificity in immunohistochemistry (19, 22, 23). The antisera used in this study are summarized in Table 1Go.


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  		TABLE 1. Antisera utilized

 
Preparation of brain tissue and immunohistochemistry
Wild-type and StAR-knockout mice were used in the present study. StAR –/– mice produce insufficient levels of adrenal steroids and typically die within 2–10 d after birth (11). Postnatal d 1 (P1) wild-type and StAR–/– (11) mice were killed and brains were fixed with 4% p-formaldehyde in phosphate buffer for at least overnight. The tissues were then incubated in a 12% sucrose solution in phosphate buffer (pH 7.4), overnight, followed by a second overnight incubation in 30% sucrose solution, both at 4 C (24). The brains were mounted in Tissue Tek O.C.T. Compound (Miles Inc., Elkhart, IN) on a chuck and after equilibration to –20 C in a cryostat, 40-µm-thick sections of the tissue were cut and stored at –20 C in a cryoprotectant solution (30% glycerol and 30% ethylene glycol in 0.2x phosphate buffer) (24).

Immunohistochemistry was performed on free-floating sections as previously described (19) using the Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA). Samples were stained with the Vector SG kit (Vector Laboratories) or 0.05% 3,3'-diaminobenzidine (Sigma-Aldrich, St. Louis, MO) in 0.01% Triton X-100 and 0.1 M Tris mixed with 0.03% H2O2 and 10 mM imidazole, and mounted. For immunofluorescence, Alexa series red 594 and green 488 dye-conjugated antirabbit and antimouse IgG (Molecular Probes, Eugene, OR) were used. Selected sections were additionally stained with Sudan Black B (Sigma-Aldrich) to mitigate autofluorescence. Labeled or stained tissue was mounted and coverslipped with Fluoromount G (EMS Sciences, Ft. Washington, PA) or Vectashield with or without 4',6-diamidino-2-phenylindole (DAPI) stain (Vector Laboratories).

Computer images of sections were taken using an Olympus BX51 microscope (Melville, NY) and the Olympus Magnifier program, Nikon (Tokyo, Japan) E800 microscope system with MetaView 5.0 software and a Zeiss (Thornwood, NY) laser scanning confocal microscope (LSM 510) system. For these studies, two to three brains mice of each group were used and experiments were replicated two to three times.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
StAR is expressed in the P1 mouse brain
Immunohistochemistry and immunofluorescence was performed using three different anti-StAR antisera to detect StAR in P1 mouse brains. One antisera is directed against a unique peptide sequence in StAR not present in MLN64. Given the difficulty encountered by earlier efforts to identify StAR in the developing brain (25), we used free-floating immunohistochemistry using 40-µm-thick frozen sections to maximize antigen accessibility and sensitivity.

Using this technique, immunostaining for StAR was observed in the neonatal mouse cortex (Fig. 1AGo). However, specific labeling was absent in tissue from StAR-knockout neonatal mice and in wild-type sections incubated without primary antisera (Fig. 1Go, B and C). StAR expression was clearly detected in other regions of the neonatal brain as well, including the hippocampus, anterior hypothalamus, septum and pons as well as the striatum (Fig. 2Go, A and B). In general, the developing hypothalamus contained little immunoreactivity. The pattern of staining between different antisera was similar. Closer inspection of individual neurons revealed punctate staining in cell bodies and processes along with nuclear exclusion, consistent with its mitochondrial localization. Nuclear exclusion of StAR immunoreactivity was confirmed by double labeling with the nuclear dye DAPI (data not shown).



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  		FIG. 1. StAR is expressed in neonatal cortex. A, Immunopositive labeling for StAR was observed in the cortex of P1 mice, in this case using antisera directed against recombinant mouse StAR (arrows indicate immunoreactive cells). Specific staining was not observed in StAR –/– (B) mice with the same antisera and in the absence of primary antisera (C). Scale bar, 100 µm.

 


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  		FIG. 2. MLN64 is expressed in the P1 brain. Immunofluorescent signals identified StAR-expressing neurons in the striatum in the presence of anti-StAR antisera (A) with apparent nuclear exclusion (arrow), whereas there was no specific labeling in the absence of primary antisera (B). Immunofluorescence revealed expression of MLN64 (C) in striatal neurons not observed without primary antisera (D). Note that in contrast to the immunostaining pattern for StAR, there is strong, perinuclear labeling for the StAR homolog (indicated by arrows). Labeling of punctate structures consistent with an endosomal localization was further observed by immunohistochemistry for MLN64 in the striatum (E and F), such as in cells indicated by arrows. Antimouse StAR antisera was used in A and antirat MLN64 antisera was used in C and E–F. Scale bars; A and B, 25 µm; C and D, 100 µm; E and F, 25 µm.

 
MLN64 is expressed in the brain in a pattern distinct from StAR
To confirm the authenticity of observed StAR labeling in the neonatal brain, tissue sections were also probed with three specific antisera against MLN64, a StAR homolog with partial sequence identity. Two antisera recognize short peptides within MLN64 that are absent in StAR.

Expression of MLN64 was detected in the brain by immunofluorescence and immunohistochemistry. MLN64 was observed in specific neuronal cell populations in various regions of the day-old brain, including the striatum (Figs. 2Go, C and F). Intracellularly, there was punctate labeling that included perinuclear foci. This pattern of staining is consistent with its proposed endosomal localization and is not observed in cells immunopositively labeled for StAR. Furthermore, we detected MLN64 expression in the adult brain and StAR-knockout tissue. Finally, StAR expression only partially colocalized with MLN64 as revealed by dual-label immunofluorescence and intracellular staining within dual-labeled cells did not appear to overlap (Fig. 3Go).



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  		FIG. 3. StAR and MLN64 are differentially expressed in the brain. The presence of MLN64 (A, green, anti-aa369–384 MLN64) and more faintly, StAR protein (B, red, antirat StAR) was identified in the adult frontal cortex by dual-label immunofluorescence. Only a few cells exhibited overlapping staining for both proteins. No specific labeling was noted in the absence of primary antisera (D–F). Scale bar, 50 µm.

 
StAR is expressed in P450scc-immunoreactive cells
To determine whether StAR is present in steroidogenic cell types, we examined whether StAR immunoreactivity is colocalized in P450scc-expressing cells. Immunochemical detection was performed using an antipeptide antisera raised against P450scc that was previously used for this purpose in the adult brain (19).

Consistent with previous data in the rat (17), expression of P450scc was found in various regions of the P1 brain. Similar to StAR immunoreactivity, P450scc immunoreactivity was detected in several neuronal populations (Fig. 4Go). In accordance with its mitochondrial localization, nuclear-excluded punctate staining was observed. Importantly, double-labeling experiments demonstrated that StAR and P450scc immunoreactivity could be colocalized to individual cells (Fig. 5Go). Thus, these immunohistochemical analyses demonstrate conclusively that StAR is produced in steroidogenic cell types in the developing brain.



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  		FIG. 4. P450scc expression in the neonatal brain. Immunoreactivity for P450scc was detected in different regions of the CNS, such as in the cortex (A) and the striatum (B). Scale bars; A, 20 µm; B, 10 µm.

 


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  		FIG. 5. StAR is expressed in P450scc-expressing neurons in the neonate. Dual-label immunofluorescence on DAPI-stained tissue (A, arrowhead identifies blue nucleus) revealed a neuron in which P450scc (B, green) and StAR (C, red) colocalized (D, yellow-brown) outside the nucleus (indicated by all three channels in E by nonoverlapping of DAPI nuclear stain), as observed with antisera directed against mouse StAR and rat P450scc. Scale bar, 15 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
StAR is essential for hormonally regulated steroid synthesis in the adrenal glands and the gonads (7). In addition, StAR mediates steroid production in steroidogenic nonhuman placenta, mouse decidua, and cardiac myocytes (7, 26, 27). The brain can also synthesize steroids de novo, but in the absence of evidence for StAR expression, the mechanism by which neurosteroid production is carried out has been unclear, leading to speculation that a StAR-independent mechanism is involved (e.g. through MLN64 or peripheral-type benzodiazepine receptor, PBR) (15, 28). However, alternative candidates have been unsatisfactory. For instance, MLN64 localizes to late endosomes, not mitochondria (16). Unlike MLN64, PBR is most frequently localized to the mitochondria. Whereas PBR has been found in steroidogenic glia, studies to date have failed to detect it in neurons other than those in the olfactory bulb. This is problematic because certain neurons can synthesize steroid de novo (Refs. 19 , 29 and 30 ; and reviewed in Refs. 31, 32, 33, 34, 35). Recently, this question was largely resolved when StAR was demonstrated to be expressed in both glial cells and neuronal steroidogenic cell types in the adult CNS (Ref. 19 ; and reviewed in Ref. 36). Here we extend these findings to show that StAR is also present in steroidogenic cells during at least one stage in brain development, in accordance with earlier findings for the rat (19, 20).

Because the level of StAR expression is low in individual cells, immunocytochemical techniques were employed to increase sensitivity and antigen accessibility for anti-StAR antisera. Using these procedures, specific StAR immunoreactivity was detected in wild-type, but not StAR-knockout murine brains. We found StAR immunoreactivity in neurons and have previously identified StAR in glial populations using rat mesencephalon cultures from 15- to 16-d-old rat embryos (19). In these latter studies, we also found that StAR protein expression could be induced in these cell types by stimulation of the cAMP pathway. The present data are further corroborated by recent studies of postnatal development in the rat (20). Altogether, these results suggest that StAR is expressed throughout many stages of CNS development into adulthood.

StAR protein was detected in many cell populations and regions of the developing CNS that synthesize StAR in the adult, including the hippocampus, thalamus, cortex, pons, and the striatum. In the adult, StAR expression in the hypothalamus was variable and low. In the day-old, the developing hypothalamus contained sparse immunostaining for StAR. In summary, StAR is expressed in several regions during development. No gross differences were observed in the expression pattern of StAR between adult and day-old tissues, although the cerebellum was not examined. These findings are essentially similar to that observed in the rat with some exceptions, such as immunoreactivity in the striatum (20). In addition, these regions have been previously shown to synthesize P450scc in adult and developing rat (17, 19, 33). In accordance with these previous studies, we detected P450scc in the neonatal mouse brain. Immunoreactivities for P450scc and StAR possessed similar intracellular labeling patterns, consistent with a mitochondrial localization. Most importantly, StAR and P450scc were coexpressed within individual neurons. This finding is consistent with our previous in vitro data with isolated embryonic glia (19). Thus, as in the adult, StAR is expressed in steroidogenic cell types (neurons and glia) in the developing brain. Previous studies have exhaustively demonstrated that the essential requirements for de novo steroid biosynthesis are nascent StAR synthesis, P450scc, and sufficient reducing equivalents for the enzymatic reaction (Refs. 6 , 18 and 37 ; and reviewed in Ref. 38). In fact, overexpression of StAR in steroidogenic cells in the absence of trophic hormonal stimulation increases the production of steroid (6). Thus, the presence of both StAR and P450scc putatively identifies cells actively engaged in neurosteroid synthesis because they express the two proteins needed to direct cholesterol precursor into the steroidogenic pathway. These findings validate the hypothesis that StAR expression is confined to cells that synthesize steroid. Whereas neurosteroidogenesis has been primarily described in glia, it is remarkable that considerable numbers of neurons express StAR and P450scc. Further studies are required to determine whether the onset of StAR expression in the CNS is coincident with P450scc embryonically [as early as embryonic d 9.5 and 10.5 in the mouse and rat, respectively (17)] and whether all P450scc-containing cells also express basally or with stimulus, StAR protein.

We further demonstrate that the StAR homolog MLN64 is expressed in the brain. The observed StAR labeling does not reflect cross-reactivity with MLN64 because there was a lack of specific, immunopositive staining in StAR-knockout tissue sections whereas MLN64 was observed. Furthermore, StAR immunoreactivity was found using an antipeptide antisera against a region of the protein that is absent in MLN64. Also, the intracellular staining patterns for StAR and MLN64 were different, with anti-MLN64 antisera prominently labeling small structures that included apparently perinuclear clusters, consistent with a localization of endogenous MLN64 to late endosomes noted previously in cancer cells that overexpress the protein (16). Additionally, MLN64 appears to be more abundant than StAR, and its expression is neither restricted to, nor detectable in, all StAR-immunopositive cells. The present data suggest that MLN64 is not directly responsible for neurosteroid production, leaving the functional importance of this putative cholesterol transport protein in the brain to be determined.

Neurosteroid biosynthesis may play an important role in CNS development (3, 5). Recent efforts have focused on the influence of neurosteroids on the plasticity of developing neurons, such as in dendritic spine formation in Purkinje cells and GABAA receptor subunit expression in and migration and development of GABAergic cortical neurons (3, 39, 40, 41). The identification of StAR in steroidogenic cells in the developing brain represents a further step toward understanding the true relevance of neurosteroid production on these processes.

Neurosteroids may also be derived from StAR-independent pathways. These poorly characterized pathways comprise a minor component of steroid synthesis in the body except in the human placenta (3). One possibility is that a proportion of steroids are generated from oxysterols. The brain produces significant levels of oxysterols, particularly 24-hydroxycholesterol (42). This is of interest because certain oxysterols not only regulate StAR expression but freely diffuse into the mitochondria and be directly converted to steroid (43). Therefore, it is possible that local oxysterol synthesis may represent an alternative means by which neurosteroid levels are regulated.

In summary, StAR protein is expressed in both neurons and glia in the developing brain. We observed StAR immunoreactivity in cells that contained P450scc, indicating an essential role for StAR in neurosteroid production. StAR expression was separable from expression of its homolog MLN64, whose presence was also detected for the first time in the mouse brain. Because StAR is essential for acute regulation of steroidogenesis in other tissues, the finding that StAR is present in the CNS suggests that the synthesis of neurosteroids is a regulated process. These data indicate that StAR is important for neurosteroid production not only in the adult brain, but during development of the brain as well.


   Acknowledgments
 
We gratefully acknowledge Dr. Bon-chu Chung (Institute of Molecular Biology, Academia Sinica, Nankang, Taiwan) who provided some of the day-old brain tissue used in these studies. We thank Alexander G. A. Smith and Shaoli Che, M.D., Ph.D. for their assistance.


   Footnotes
 
This research was supported in part by the Alzheimer’s Association IIRG-02-3857 (to S.D.G.), and National Institutes of Health Grants DK61548 (to S.R.K.), NS43939 (to S.D.G.), CA94520 (to S.D.G.), and DK54028 (to K.L.P), and the Lalor Foundation and the International Society for Sexual and Impotence Research (S.R.K.). Part of this work was presented at the 83rd Annual Meeting of The Endocrine Society, Denver, CO, 2001.

Abbreviations: aa, Amino acids; CNS, central nervous system; DAPI, 4',6-diamidino-2-phenylindole; MLN64, metastatic lymph node 64; P1, postnatal d 1; PBR, peripheral-type benzodiazepine receptor; StAR, steroidogenic acute regulatory.

Received December 23, 2003.

Accepted for publication June 8, 2004.


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 Introduction
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 Results
 Discussion
 References
 

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