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Nonclassical Testosterone Signaling: A New Pathway Controlling Spermatogenesis?1

Testosterone is the essential regulator of spermatogenesis [1]. Produced by the testicular Leydig cells in response to pituitary luteinizing hormone (LH) stimulation, testosterone mediates its effects by binding to its cognate receptor, the ligand-activated transcription factor NR3C4, also known as the androgen receptor (AR). The role of testosterone in promoting spermatogenesis was established in experiments using systemic blockade of AR signaling or suppression of testosterone production [2], either of which leads to complete arrest of spermatogenesis during meiosis. It is also now commonly accepted that AR is widely expressed in the somatic cells but not the germ cells of the adult testis. However, it is only in the past decade, with the development and wide exploitation of cell-specific AR knockout (ARKO) mice, that we have begun to unravel the specific intracellular mechanisms involved in vivo. Several groups have now independently shown that testosterone signaling through AR specifically within Sertoli cells is essential for postmeiotic germ cell development [3–6]; so our understanding is complete, yes? Well no, it would appear we still have much to learn. Because of the well-established role of AR as a transcription factor, almost all interpretations of testosterone impacts have been via modulation of the transcription of AR target genes, many of which have been identified by scanning for the presence of androgen response elements in their noncoding regions. This well-established and extremely well-studied pathway, which can take hours to show a response, has become known as the classical androgen-signaling pathway (Fig. 1). However, back in 2004, Sertoli cells isolated from rats were shown in vitro to also respond to testosterone stimulation by rapidly activating the MAP-kinase signaling pathway (within 1 min) and CREB transcription factor, in an AR-dependent signaling cascade [7], providing evidence that testosterone can also act in Sertoli cells in a fast, so-called nonclassical manner. Despite an increasing body of circumstantial evidence amassed over the past decade (reviewed in [8]), it has remained unknown whether testosterone does act via this nonclassical pathway in vivo, and if so, what impact it has on spermatogenesis. An unanticipated issue arising from the design of the in vivo cell-specific ablation models of AR is that these knockout models simultaneously destroy signaling via both classical and nonclassical pathways, making it impossible to dissect out and assign specific functions to each pathway. In a groundbreaking paper in a recent issue of Biology of Reproduction, Toocheck and colleagues [9] have instead used specific inhibitors and activators of either classical or nonclassical testosterone signaling to show that these pathways perform