Abstract
The nuclear receptor steroidogenic factor 1 (SF-1, AD4BP, NR5A1) is a key regulator of the endocrine axes and is essential for adrenal and gonad development. Partial rescue of Nr5a1(-/-) mice with an SF-1-expressing transgene caused a hypomorphic phenotype that revealed its roles in Leydig cell development. In contrast to controls, all male rescue mice (Nr5a1(-/-);tg(+/0)) showed varying signs of androgen deficiency, including spermatogenic arrest, cryptorchidism, and poor virilization. Expression of various Leydig cell markers measured by immunohistochemistry, Western blot analysis, and RT-PCR indicated fetal and adult Leydig cell development were differentially impaired. Whereas fetal Leydig cell development was delayed in Nr5a1(-/-);tg(+/0) embryos, it recovered to control levels by birth. In contrast, Sult1e1, Vcam1, and Hsd3b6 transcript levels in adult rescue testes indicated complete blockage in adult Leydig cell development. In addition, between Postnatal Days 8 and 12, peritubular cells expressing PTCH1, SF-1, and CYP11A1 were observed in control testes but not in rescue testes, indicating SF-1 is needed for either survival or differentiation of adult Leydig cell progenitors. Cultured prepubertal rat peritubular cells also expressed SF-1 and PTCH1, but Cyp11a1 was expressed only after treatment with cAMP and retinoic acid. Together, data show SF-1 is needed for proper development of fetal and adult Leydig cells but with distinct primary functions; in fetal Leydig cells, it regulates differentiation, whereas in adult Leydig cells it regulates progenitor cell formation and/or survival.
Highlights
Steroidogenic factor 1 (SF-1, AD4BP, NR5A1) is a member of the nuclear receptor family that is essential for development and function of the adrenal and gonadal endocrine systems [1,2,3,4]
SF-1 expression and function are primarily restricted to the adrenal gland and the hypothalamic-pituitarygonadal axis, where it acts in support of steroidogenic cell lineages of the gonads, adrenocortical cells, pituitary gonadotropes, and the ventromedial hypothalamus and to regulate tissue-specific transcription of genes required for hormone production and development [11,12,13,14,15]
Similarities between the findings suggested a connection between Desert hedgehog (DHH) produced by Sertoli cells and SF-1-positive peritubular cells in adult Leydig cells (ALCs) development
Summary
Steroidogenic factor 1 (SF-1, AD4BP, NR5A1) is a member of the nuclear receptor family that is essential for development and function of the adrenal and gonadal endocrine systems [1,2,3,4] Studies in both mice and humans link SF-1 mutations to XY. Other models of SF-1 deficiency, including conditional deletions, compound mutations, and haploinsufficiency, were developed and used to gain deeper insight into its functions [19,20,21,22,23,24,25] Some of these implicated SF-1 in Leydig cell development, direct evidence and details are still missing
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