Regulation of Translocator Protein 18 kDa (TSPO) Expression in Rat and Human Male Germ Cells.

Gurpreet Manku,Martine Culty

doi:10.3390/ijms17091486

Abstract

Translocator protein 18 kDa (TSPO) is a high affinity cholesterol- and drug-binding protein highly expressed in steroidogenic cells, such as Leydig cells, where it plays a role in cholesterol mitochondrial transport. We have previously shown that TSPO is expressed in postnatal day 3 rat gonocytes, precursors of spermatogonial stem cells. Gonocytes undergo regulated phases of proliferation and migration, followed by retinoic acid (RA)-induced differentiation. Understanding these processes is important since their disruption may lead to the formation of carcinoma in situ, a precursor of testicular germ cell tumors (TGCTs). Previously, we showed that TSPO ligands do not regulate gonocyte proliferation. In the present study, we found that TSPO expression is downregulated in differentiating gonocytes. Similarly, in F9 embryonal carcinoma cells, a mouse TGCT cell line with embryonic stem cell properties, there is a significant decrease in TSPO expression during RA-induced differentiation. Silencing TSPO expression in gonocytes increased the stimulatory effect of RA on the expression of the differentiation marker Stra8, suggesting that TSPO exerts a repressive role on differentiation. Furthermore, in normal human testes, TSPO was located not only in Leydig cells, but also in discrete spermatogenic phases such as the forming acrosome of round spermatids. By contrast, seminomas, the most common type of TGCT, presented high levels of TSPO mRNA. TSPO protein was expressed in the cytoplasmic compartment of seminoma cells, identified by their nuclear expression of the transcription factors OCT4 and AP2G. Thus, TSPO appears to be tightly regulated during germ cell differentiation, and to be deregulated in seminomas, suggesting a role in germ cell development and pathology.

Highlights

Translocator protein 18 kDa (TSPO; previously known as peripheral benzodiazepine receptor PBR) is a high affinity drug- and cholesterol-binding protein strongly expressed in steroidogenic cells, including testicular Leydig cells, where it is located at the outer mitochondrial membrane (OMM) [1,2,3]
We have previously shown that Translocator protein kDa (TSPO) is expressed in the nucleus of PND3 gonocytes but that binding of its drug ligand does not affect gonocyte proliferation
These data suggested that TSPO is actively down-regulated during gonocyte differentiation

Summary

Introduction

Translocator protein 18 kDa (TSPO; previously known as peripheral benzodiazepine receptor PBR) is a high affinity drug- and cholesterol-binding protein strongly expressed in steroidogenic cells, including testicular Leydig cells, where it is located at the outer mitochondrial membrane (OMM) [1,2,3]. We previously made the serendipitous observation that TSPO was present in neonatal rat gonocytes ( known as pre- and pro-spermatogonia), the precursor cells of type A spermatogonia, including cells of the first spermatogenic wave and spermatogonial stem cells (SSCs) [8]. TSPO was found in pachytene spermatocytes and dividing spermatogonia in adult rat testis [8]. We found that TSPO transcripts are abundant in adult mouse spermatogonia, pachytene spermatocytes and round spermatids, while the protein is observed in mouse sperm [9]

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