Postnatal ontogeny of the glucocorticoid receptor in the hippocampus.

Corticosteroid hormones are important intrinsic factors that not only mediate the response to stress but also largely contribute to the main physiological processes. The biological actions of these steroids involve, first of all, the activation of specific receptors, namely mineralocorticoid (MR) and glucocorticoid (GR) receptors. These two receptor types govern a flexible and well-balanced mechanism that leads to the often opposing changes in the cell. The hippocampus is the central part of the extrahypothalamic feedback loop in the control of the hypothalamic-pituitary-adrenal (HPA) axis activity. The coexpression of both MR and GR in the hippocampus serves a coordinated response to corticosteroids in the hippocampal neurons, thereby mediating the neuronal excitability, stress response, and behavioral adaptation. Each receptor type reveals distinct ontogenetic pattern over the postnatal period. This review addresses the issues relating to postnatal development of the HPA axis and especially the hippocampal expression of the GR proteins in intact and prenatally stressed rats.

E3 ubiquitin ligase RNF31 cooperates with DAX-1 in transcriptional repression of steroidogenesis.

Genetic and experimental evidence points to a critical involvement of the atypical mammalian orphan receptor DAX-1 in reproductive development and steroidogenesis. Unlike conventional nuclear receptors, DAX-1 appears not to function as a DNA-bound transcription factor. Instead, it has acquired the capability to act as a transcriptional corepressor of steroidogenic factor 1 (SF-1). The interplay of DAX-1 and SF-1 is considered a central, presumably ligand-independent element of adrenogonadal development and function that requires tight regulation. This raises a substantial interest in identifying its modulators and the regulatory signals involved. Here, we uncover molecular mechanisms that link DAX-1 to the ubiquitin modification system via functional interaction with the E3 ubiquitin ligase RNF31. We demonstrate that RNF31 is coexpressed with DAX-1 in steroidogenic tissues and participates in repressing steroidogenic gene expression. We provide evidence for the in vivo existence of a corepressor complex containing RNF31 and DAX-1 at the promoters of the StAR and CYP19 genes. Our data suggest that RNF31 functions to stabilize DAX-1, which might be linked to DAX-1 monoubiquitination. In conclusion, RNF31 appears to be required for DAX-1 to repress transcription, provides means to regulate DAX-1 in ligand-independent ways, and emerges as a relevant coregulator of steroidogenic pathways governing physiology and disease.

Expression of glucocorticoid receptors in the hippocampal region of the rat brain during postnatal development.

Circulating glucocorticoids, of which their concentration is largely under the control of the hypothalamic-pituitary adrenal (HPA) axis, acting through the glucocorticoid receptors (GR) regulate a large variety of pivotal functions of the organism such as growth, development, immune- and stress-response. The main mechanism of regulation of the HPA axis activity is via negative feedback at all levels of the HPA axis itself as well as at the extra-hypothalamic level, a central part of which is the hippocampus. During neonatal development, the HPA axis of rats undergoes a period of hyporesponsiveness (SHRP)-when most stress stimuli fail to induce stress-response. Here, we describe the pattern of GR proteins expression in the hippocampal area of the rat brain during postnatal development and in adulthood. We demonstrated that the GR protein, of which its expression level is gradually enhanced in the hippocampus during postnatal life, exists in three different molecular sized forms. A larger molecular form was expressed at rather high levels at all studied time periods. A second smaller variant of GR was transiently expressed during the first one and a half weeks that corresponds with SHRP and then appeared again only in the adulthood. By the end of SHRP on PD 13, third smallest protein form of GR started to be detected in the hippocampal area. Thus, it remains to be disclosed in the nearest future, how the hippocampal GR isoforms may be involved in regulation of the neonatal HPA axis hyporesponsiveness as well as in functions of this system during the ensuing period of the brain maturation.

Comparative distribution of the mammalian mediator subunit thyroid hormone receptor-associated protein (TRAP220) mRNA in developing and adult rodent brain.

TRAP220 (thyroid hormone receptor-associated protein) is a recently cloned nuclear receptor coactivator, which interacts with several nuclear receptors in a ligand-dependent manner and stimulates transcription by recruiting the TRAP mediator complex to hormone responsive promoter regions. TRAP220 has been shown to interact with thyroid hormone receptors, vitamin D receptors, peroxisome proliferator-activated receptors, retinoic acid receptors and oestrogen receptors. Thyroid hormone and retinoic acid play very important roles in brain development and they also influence adult brain. Using in situ hybridization we have examined expression of TRAP220 mRNA in the central nervous system during development and in adult rat and mouse brain. Expression of TRAP220 was seen already during early embryonic development in the epithelium of neural tube at E9 in mouse and at E12 in rat. At later stages of development the strongest signal was seen in different layers of cerebral neocortex, external germinal layer of cerebellum, differentiating fields of hippocampus and neuroepithelium, and a moderate signal was detected in basal ganglia, different areas of diencephalon and midbrain. In adult rat brain the signal was more restricted than during development. TRAP220 expression occurred mostly in the granular layer of cerebellar cortex, piriform cortex and hippocampal formation. The signal was found predominantly in neurons. Our work supports the assumption that TRAP220 plays an important role in growth and differentiation of central nervous system and may have a function in certain areas of adult brain.