Identification of a novel population of adrenal-like cells in the mammalian testis

Abstract

Steroidogenic cells of the adrenal and gonad are thought to be derived from a common primordium that divides into separate tissues during embryogenesis. In this paper, we show that cells with mixed adrenal and Leydig cell properties are found dispersed in the insterstitium of the embryonic and adult mouse testis. They express the adrenal markers Cyp11b1 and Cyp21 and respond to ACTH. Consistent with these properties, we show that the embryonic testis produces the adrenal steroid corticosterone. These cells also express Cyp17 and respond to hCG stimulation but do not express the Leydig specific marker Insl3 showing that they are a population of steroidogenic cells distinct from Leydig cells. Based on their properties, we refer to these cells as adrenal-like cells of the testis and propose that they are the mouse equivalent of the precursors of human adrenal rests, tumors found primarily in male patients with congenital adrenal hyperplasia. Organ culture studies show that ACTH-responsive cells are present at the gonad/mesonephros border and seem to migrate into the XY but not the XX gonad during development. Consistent with this, using transgenic Cyp11a1 reporter mice, we definitively show that steroidogenic cells can migrate from the mesonephros into the XY gonad. We also show that the region between the mesonephros and the gonad harbors steroidogenic cell precursors that are repressed by the presence of the mesonephros. We propose that this region is the source of the adrenal-like cells that migrate into the testis as it develops and are activated when Leydig cells differentiate. These studies reveal the complex nature of steroidogenic cell differentiation during urogenital development.

Gene dosage effects and transcriptional regulation of early mammalian adrenal cortex development

“…Even though the specificity of expression is relatively strict in adult tissues, numerous reports have shown that some gonadspecific enzymes are expressed in the adrenal during development. Conversely, adrenal enzymes were observed in the developing gonad [9][10][11][12][13][14]. This suggests that, in agreement with histological studies, the adrenal cortex and gonads have a common embryological origin.…”

“…M a n u s c r i p t 8 Therefore it is tempting to speculate that Dax1 prevents adrenal differentiation in the cells of the AGP that are targeted to gonad fate. We previously described cells with adrenal markers expression -the so-called adrenal-like cells-within the testicular interstitium during embryonic development and after birth [14]. It would be interesting to investigate If Dax1 prevents adrenal differentiation in the AGP, by analysing the population of adrenal-like cells in the Dax1 mutant gonads of both sexes, which should be expanded.…”

An adrenal rest tumour in the perirenal region in a patient with congenital adrenal hyperplasia due to congenital 3β-hydroxysteroid dehydrogenase deficiency

“…It is hypothesized that in the presence of high plasma POMC concentrations, these cells can proliferate leading to the development of adrenal rest tumours. Interestingly, in a recent study, Val et al describe a novel population of adrenal-like cells in the mouse testis originating from adreno-gonadal primordial steroidogenic cells (15). They speculate that TART in CAH patients may have their origin from these tissues.…”

Congenital Adrenal Hyperplasia, the Origin of Combined Infertility: A Case Report and a Review of Literature

“…The adrenal-like cells express steroidogenic enzymes such as 11β-OH, 17α-OH or 21-OH and respond to ACTH, however, they do not express Leydig cell specific markers. Such a cell population has not been identified yet in human testis [37]. The tumors express adrenal enzymes and ACTH as well as angiontensin receptors.…”