Progesterone Stimulates the Activity of the Promoters of Peripheral Myelin Protein‐22 and Protein Zero Genes in Schwann Cells

Abstract

To understand better the mechanisms by which progesterone (PROG) promotes myelination in the PNS, cultured rat Schwann cells were transiently transfected with reporter constructs in which luciferase expression was controlled by the promoter region of either the peripheral myelin protein-22 (PMP22) or the protein zero (F 0) genes. PROG stimulated the P0 promoter and promoter 1, but not promoter 2, of PMP22. The effect of PROG was specific, as estradiol and testosterone only weakly activated promoters. Dose-response curves for stimulation of both promoter constructs by PROG were biphasic. RU486, a FROG antagonist, did not abolish the effect of PIROG, but stimulated promoter activities by itself. In the human carcinoma cell line T47D expressing high levels of FROG receptor, PROG did not stimulate the P0 and PMP22 promoters, whereas the promoter region of the mouse mammary tumor virus was fully activated. Thus, the activation by FROG of promoter activity of two peripheral myelin protein genes is Schwann-celI specific. Key Words: Progesterone-Schwann cell-P0 and peripheral myelin protein-22 gene promoters.

Progesterone Synthesized by Schwann Cells during Myelin Formation Regulates Neuronal Gene Expression

“…Progesterone causes an approximate 2-fold stimulation of a luciferase reporter gene under the control of the promoter regions of PMP22 and P 0 in Schwann cell cultures (Desarnaud et al, 1998). The stimulation was not inhibited by RU-486, but rather RU-486 acted as an agonist under the conditions of the experiments.…”

“…Specifically, hormones such as thyroid hormones and corticosteroids have been implicated in regulating the differentiation of glial cells, suggesting a role for various hormones in the myelination process (Walters and Morell, 1981;Almazan et al, 1985;Koper et al, 1986;Warringa et al, 1987;Kumar et al, 1989;Tosic et al, 1992;Barres et al, 1994). Estradiol and progesterone have also been implicated in increasing the expression of myelin proteins (Jung-Testas et al, 1994;Robel and Baulieu, 1994;Koenig et al, 1995;Jung-Testas et al, 1996b;Notterpek et al, 1999), while progesterone and dexamethasone have been found to activate the promoters of peripheral myelin protein-22 and P 0 (Desarnaud et al, 1998;Melcangi et al, 1999). The enzymes responsible for progesterone biosynthesis, cytochrome P450scc and 3␤-HSD, have been identified in the brain and spinal cord of the rat.…”

P2X7-mediated Increased Intracellular Calcium Causes Functional Derangement in Schwann Cells from Rats with CMT1A Neuropathy

“…PMP22 expression was reported to be stimulated by progesterone and by cAMP (43,44). Accordingly, recent studies have shown that progesterone antagonists and ascorbic acid, which inhibits the stimulatory effect of cAMP on PMP22 expression, reduce the levels of PMP22 and improve the phenotype in animal models of CMT1A (45,46).…”

Neurosteroid regulation of central nervous system development

“…In parallel studies, another group showed that progesterone, as well as dexamethasone, enhanced both the rate of myelin synthesis and accelerated the time of initiation of myelin synthesis (Chan et al, 1998). Progesterone has also been shown to increase mRNAs for myelin-specific proteins, including protein 0 (P0) and the peripheral myelin protein-22 (PMP-22) (Desarnaud et al, 1998;Melcangi et al, 1998;Melcangi et al, 1999;Notterpek et al, 1999), as well as increasing the expression of Krox-20, a transcription factor that is crucial for myelination in the peripheral nervous system . In co-cultures of Schwann cells and neurons, progesterone increased the rate of myelin synthesis in a dose-dependent manner.…”