Developmental expression of cell cycle regulators in the baboon fetal adrenal gland

Abstract

Although the human and the nonhuman primate fetal adrenal glands undergo a highly unique pattern of cortical zonespecific intrauterine growth and development, studies of the regulatory components of the cell cycle responsible for this growth have not been conducted. Therefore, the present study determined expression of the cell cycle regulators, cyclin D1 and cyclin E, and their cyclin-dependent kinases, Cdk2, Cdk4, and Cdk6, and Ki67 a marker of cell proliferation within the baboon fetal adrenal cortex during advancing stages of gestation. Fetal adrenal glands were obtained on days 60 (early), 100 (mid), and 160-170 (late) of gestation (termZ184 days). Mean (GS.E.) cyclin D1 mRNA levels, determined by RT-PCR and expressed relative to 18S rRNA, were similar at early (0 . 85G0 . 09) and mid (1 . 04G 0 . 08) gestation, then decreased (P!0 . 001, ANOVA) approximately 50% by late gestation (0 . 57G0 . 04). Cyclin E mRNA levels were also similar at early (2 . 03G0 . 07) and mid (1 . 63G0 . 31) gestation, and decreased by 70% (P!0 . 001) in late gestation (0 . 53G0 . 09). Coinciding with the decrease in cyclin D1 and cyclin E, the percentage of Ki67 positive cells in the definitive zone decreased twofold (P!0 . 01) between mid (28 . 2G3 . 6) and late (13 . 8G1 . 7) gestation. The cyclin D1 and cyclin E proteins, determined by immunocytochemistry, were expressed at high levels in the definitive zone of baboon fetal adrenal gland, where they decreased between mid-and late gestation. In contrast, immunocytochemical expression of the functionally important steroidogenic enzyme D 5 -3b-hydroxysteroid dehydrogenase (3b-HSD) became abundant in the definitive and transitional zones with advancing pregnancy. However, fetal adrenal Cdk2, Cdk4, and Cdk6 mRNA levels and protein immunoexpression were similar in the baboon fetal adrenal at early-, mid-, and late gestation. In summary, expression of cyclin D1, cyclin E, and Ki67 decreased, while 3b-HSD expression increased, in the fetal adrenal cortex, particularly in the definitive zone, between mid-and late-baboon gestation. We propose that a developmental decline in cellular proliferation permits functional differentiation of fetal adrenal cortical cells, leading to increased production of steroid hormones important for placental estrogen synthesis and maturation of organ systems within the developing fetus.

Cyclin D1 regulates hepatic estrogen and androgen metabolism

“…A handful of prior studies have suggested a link between the cell cycle machinery and sex steroid metabolism, although a causative role has not been previously established. For example, in the fetal baboon adrenal gland, cyclin D1 expression decreases during gestation whereas 3␤-HSD expression increases (14). Treatment of human ovarian cells with the anti-proliferative agents TGF-␤1 and all-trans retinoic acid induces HSD3B1 expression, suggesting that cell cycle inhibition promotes its expression (36).…”

Efeitos in vivo do ACTH e do peptídeo N-POMC na expressão de proteínas e genes relacionados com o controle do ciclo celular em adrenais de ratos.

“…It has been observed that the levels of cyclin D1 did not change in the adrenal gland of sheep fetuses after administration of N-POMC 1-77 and N-POMC 1-49 peptides (Coulter et al, 2002). In contrast, in a study done in baboons, the expression of cyclin D1, cyclin E, and Ki67 decreased, while the 3 beta-HSD expression increased, in the fetal adrenal cortex, particularly in the definitive zone, between the mid and late baboon gestational period (Dumitrescu et al, 2007). Furthermore, the action of angiotensin II on the human NCI-H295 adrenocortical carcinoma cell line correlates with the expression of cyclin D1 in the proliferative response triggered by this hormone (Watanabe et al, 1996).…”