Nuclear Progesterone Receptors Are Up-Regulated by Estrogens in Neurons and Radial Glial Progenitors in the Brain of Zebrafish

Nicolas Diotel,Yong Zhu,Isabelle Anglade,Elisabeth Pellegrini,Arianna Servili,Marie-Madeleine Gueguen,Colette Vaillant,Olivier Kah,Svetlana Mironov,Vincent Laudet

doi:10.1371/journal.pone.0028375

Abstract

In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr) has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation.

Highlights

In adult vertebrates, production of sex steroids has long been considered to be restricted to the gonads and, on a lower level, the adrenals
It is acknowledged that de novo synthesis of steroids from cholesterol occurs within the brain
While many studies have focused on the feedback effects of sex steroids on the organization and regulation of neuroendocrine and behavioral circuits, there is increasing interest for non-reproductive functions of steroids in the brain, notably on neurogenesis and brain repair

Summary

Introduction

Production of sex steroids has long been considered to be restricted to the gonads and, on a lower level, the adrenals. The evidence is based on the fact that all steroidogenic enzymes are expressed in the brain and exhibit biological activity The synthesis of such ‘‘neurosteroids’’ was initially demonstrated in mammals and subsequently in other vertebrates [1,2,3,4,5,6,7]. While many studies have focused on the feedback effects of sex steroids on the organization and regulation of neuroendocrine and behavioral circuits, there is increasing interest for non-reproductive functions of steroids in the brain, notably on neurogenesis and brain repair. This is the case of estrogens and progesterone, whose effects on brain development and brain repair are more and more studied [8,9]. There is indication that neuroprotective effects of progesterone could be mediated by various mechanisms such as reduction of neuronal vulnerability to neurotoxic molecules [19], reduction of cell loss, inhibition of lipid peroxidation and expression of proinflammatory genes [11,20]

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