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Endocrinology Vol. 148, No. 10 4557-4559
Copyright © 2007 by The Endocrine Society

Retinoid Inactivation: Survival Factor for Male Germ Cells

William S. Blaner and Cathy L. Mendelsohn

Departments of Medicine (W.S.B.), Genetics and Development (C.L.M.), and Pathology (C.L.M.), College of Physicians and Surgeons, Columbia University, New York, New York 10032

Address all correspondence and requests for reprints to: William S. Blaner, Ph.D., Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032. E-mail: wsb2{at}columbia.edu.

Retinoids (vitamin A and its natural and synthetic analogs) act to regulate many developmental processes (1, 2). Several recent publications have provided compelling evidence that modulation of retinoic acid levels during fetal gonad development provides a molecular control mechanism that specifies germ cell fate (3, 4). The findings of MacLean et al. (5) reported in this issue of Endocrinology establish that the enzyme CYP26B1, which catalyzes the oxidative metabolism (catabolism) of retinoic acid, maintains low levels of retinoic acid within the developing mouse testis. This action by CYP26B1 at embryonic d 13.5 prevents entry of male germ cells into meiosis and blocks apoptosis of the germ cells (5). Collectively, the data of MacLean et al. (5) demonstrate that CYP26B1 activity is required for germ cell survival in the embryonic testes.

Retinoic acid is a potent transcriptional regulator whose actions are mediated through two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) (1, 2, 6). In excess of 500 genes may be responsive to retinoic acid (7). When retinoic acid is not available, RAR/RXR heterodimers bind to retinoic acid response elements within the promoters of genes and form protein-protein complexes with transcriptional corepressors, resulting in chromatin condensation and transcriptional silencing. In the presence of retinoic acid corepressors are released from the RAR/RXR heterodimer, which is now free to recruit and bind coactivators resulting in chromatin decondensation and transcriptional activation. Clearly the amount of retinoic acid present in a cell will be a critical factor for determining whether a retinoid-responsive gene will be silenced or activated. Thus, the establishment of an appropriate metabolic balance between retinoic acid synthesis and degradation within a cell or tissue is essential to the regulation of retinoic acid-responsive gene expression.

The metabolism of retinoic acid is complex and involves many enzymes and binding proteins that are specific to this metabolism. A simplified scheme depicting retinoic acid synthesis and catabolism within a cell is provided in Fig. 1Go. The formation of retinoic acid from the more abundant retinoid precursors retinol and retinyl ester is thought to be catalyzed by a number of retinol dehydrogenases and retinaldehyde dehydrogenases as well as possibly a number of other enzymes (8, 9, 10, 11). The best characterized of these retinoic acid synthesizing enzymes are the retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2, and ALDH1A3), which are members of the aldehyde dehydrogenase family of enzymes and are known to have important roles in assuring normal embryologic development (10, 11). The elimination of retinoic acid is catalyzed via the actions of a family of cytochrome P450 enzymes, CYP26A1, CYP26B1, and CYP26C1, which convert retinoic acid to more polar metabolites that can be readily excreted from the body (12, 13, 14, 15, 16). The gene for one of these enzymes, Cyp26B1, is expressed in somatic cells of the embryonic testis (3, 17). In their report, MacLean et al. (5) describe the generation and use of Cyp26B1-null (Cyp26B1–/–) mice to study the role of retinoic acid in mediating normal testes development.


Figure 1
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  		FIG. 1. Metabolic pathway for the formation and degradation of retinoic acid. All retinoid must be acquired from the diet as either retinyl ester or retinol or as dietary provitamin A carotenoids like ß-carotene, which are converted within the body to retinaldehyde. These dietary forms can undergo enzymatic oxidation to form retinoic acid, which regulates transcriptional activity through its nuclear receptors, the RARs and RXRs. Retinoic acid undergoes further oxidation via the actions of cytochrome P450 enzymes like CYP26A1, CYP26B1, and CYP26C1. Most, if not all, of the oxidized metabolites of retinoic acid are destined for elimination from the cell or tissue. However, some of these metabolites have been reported to have transcriptional activity, but it remains unclear whether this activity is physiologically significant.

 
Retinoids have long been known to play an essential role in maintaining male fertility. Nutritional studies in rats and genetic studies in mice demonstrate a requirement for retinoic acid at prepuberty for initiation of spermatogenesis and in adults for maintenance of spermatogenesis and for maturation of spermatozoa in the epididymis (18, 19, 20, 21, 22, 23, 24). The studies of MacLean et al. (5) and those of Bowles et al. (3) indicate that retinoid signaling is also important in the fetal gonad for sex determination and for germ cell survival. Primordial germ cells migrate into the genital ridge in mice between embryonic d 10 and 11. The subsequent decision of whether these cells should pause or progress through meiosis determines whether these cells will give rise to male or female gonads. In males, the germ cells do not progress through meiosis until after birth; whereas, in females, germ cells immediately undergo oogenesis, enter meiosis, and progress until the diplotene stage after which they arrest until puberty (25). Several lines of evidence suggest that the default pathway of germ cells is entry into meiosis and that in males, this pathway is normally blocked by signals from the genital ridge which are present at embryonic d 12 (25). The signals controlling progression through meiosis and the choice between oogenesis and spermatogenesis reside in the genital ridge. Until recently these signals have not been known. The work of MacLean et al. (5) and Bowles et al. (3) provides new insights into the origin and biochemical nature of these signals.

Key observations made by MacLean et al. (5) from their study of Cyp26B1–/– mice include the finding that Cyp26B1–/– mice have increased retinoic acid levels in the embryonic testes and that Cyp26B1–/– germ cells prematurely enter meiosis at embryonic d 13.5 but arrest at the pachytene stage. In addition, after embryonic d 13.5, the male germ cells present in Cyp26B1–/– mice show a markedly increased rate of apoptosis that results in the near complete absence of germ cells in male neonates. Unlike germ cell differentiation, Sertoli and Leydig cell differentiation is normal in Cyp26B1–/– mice. Ovarian germ and somatic cells are reported also to be unaffected by the absence of CYP26B1. When the synthetic retinoic acid agonist Am580, which is resistant to CYP26 catalyzed catabolism, was administered to cultured wild-type embryonic mouse testes it rapidly induced meiosis of the germ cells. This suggests that the abnormal development of germ cells in Cyp26B1–/– testes arises from excessive retinoic acid accumulation rather than from the absence of CYP26B1. Collectively, these findings allow MacLean et al. (5) to reach the conclusion that CYP26B1 acts in the embryonic testes to maintain low levels of retinoic acid, which blocks entry into meiosis and acts as a survival factor to prevent apoptosis of male germ cells.

The new findings of MacLean et al. (5) extend earlier published work, which established that expression of Stra8 (a gene needed for meiotic initiation), Scp3 (a gene that encodes a component of the synaptonemal complex), and Dmc1 (a gene encoding a meiosis-specific recombinase) are up-regulated in the embryonic mouse testes in response to retinoic acid administration and in Cyp26B1–/– embryonic testes (3, 4). This earlier published work strongly suggested a linkage among retinoic acid, CYP26B1, and prevention of premature meiosis in embryonic male germ cells. The present work of MacLean et al. (5) establishes that CYP26B1 affords a metabolic barrier in the embryonic testes, which maintains the viability of male germ cells during embryonic development by keeping the germ cells in mitotic quiescence until meiosis is required for spermatogenesis.


   Footnotes
 
Abbreviations: ALDH, Aldehyde dehydrogenase; RAR, retinoic acid receptor; RXR, retinoid X receptor.

Received June 29, 2007.

Accepted for publication July 2, 2007.


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