Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system

Compagnone, Nathalie A.

doi:10.1210/en.136.11.5212

Cited by 128 publications

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“…The finding that both enzymes were expressed strongly in the fetal brain and adrenal gland is consistent with our previous observations (Nguyen et al 2003a, c) and studies in rodents by others (Voutilainen & Miller 1986, Compagnone et al 1995, Narasaka et al 2001. Expression of P450 scc was significantly decreased in the adrenal gland after hypophysectomy, consistent with the stimulatory role of ACTH in the regulation of adrenal expression of P450 scc and production of pregnenolone in the fetus (Simmonds et al 2001).…”

Section: Discussionsupporting

confidence: 91%

Hypothalamic pituitary adrenal axis

Moreland¹

Rheumatology and Immunology Therapy

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Neuroactive steroids may be synthesised in the brain either de novo from cholesterol or from blood-borne precursors. Concentrations of a GABA A receptor agonist, allopregnanolone, in the fetal brain exceed those in the circulation, and are markedly higher than adult brain concentrations. We used fetal hypophysectomy or adrenalectomy to elucidate the contribution of hypothalamic-pituitary factors and adrenal steroid secretion to the overall neuroactive steroid level in both the fetal brain and the fetal circulation. Hypophysectomy or adrenalectomy was performed between 108 and 112 days of gestation (term 147 days) and fetal tissues were collected at 140 days of gestation. Immunoreactive (ir) ACTH and cortisol in the plasma were significantly reduced after hypophysectomy, whereas adrenalectomy led to increased irACTH but significantly decreased cortisol concentrations, as expected. Brain concentrations of allopregnanolone, progesterone and pregnenolone did not change significantly in fetuses that underwent either hypophysectomy or adrenalectomy; however, concentrations in the plasma and content in the adrenal gland were decreased. Expression of cytochrome P450 scc and 5 -reductase type II (5 RII) in the brain, measured by western immunoblotting, did not change after either hypophysectomy or adrenalectomy but, after hypophysectomy, expression of P450 scc in the adrenal gland was significantly decreased and that of 5 RII remained unchanged. These findings suggest that the regulation of the neuroactive steroid content in the fetal brain is independent of adrenal steroidogenesis and hypothalamic-pituitary factors. Furthermore, the absence of a change in enzyme expression in the brain suggests that the control of the expression of these enzymes is independent of hypothalamic-pituitary factors. Thus local control mechanisms within the brain may be responsible for maintaining the high neurosteroid content present during fetal life, as these mechanisms are independent of adrenal steroid production.

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Section: Discussionsupporting

confidence: 91%

Hypothalamic pituitary adrenal axis

Moreland¹

Rheumatology and Immunology Therapy

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“…P450c17, the enzyme that is required for synthesis of DHEA from pregnenolone, is found in specific neurons of embryonic rodent brains (Compagnone et al, 1995b). P450c17 expression is mainly neuronal; its expression can be found as early as embryonic day 9.5, and persists in the central nervous system during development.…”

Section: General Overviewmentioning

confidence: 99%

Neurosteroid regulation of central nervous system development

Mellon

2007

Pharmacology & Therapeutics

189

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Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABA A and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids -pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone.

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“…Male and female affected infants lack cortisol production and are hypertensive. To determine the location of P450c17 expression during early embryonic development in wild-type mice, we performed timed matings of superovulated female mice, obtained E7.0 embryos, and analyzed these embryos by immunocytochemistry with an antibody to human P450c17 that readily and specifically detects mouse P450c17 (12). P450c17 was detected in the embryonic endoderm of E7.0 embryos (Fig.…”

Section: Creation Of Gene-targeted Micementioning

confidence: 99%

“…P450c17 is also expressed in the fetal mouse brain beginning at embryonic day 9.5 (E9.5) (12). At this time, P450c17 is found in cells migrating from the neural crest, and subsequently, P450c17 is found in many cells derived from the neural crest.…”

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Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Bair

Mellon

2004

Molecular and Cellular Biology

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Dehydroepiandrosterone (DHEA), a 19-carbon precursor of sex steroids, is abundantly produced in the human but not the mouse adrenal. However, mice produce DHEA and DHEA-sulfate (DHEAS) in the fetal brain. DHEA stimulates axonal growth from specific populations of mouse neocortical neurons in vitro, while DHEAS stimulates dendritic growth from those cells. The synthesis of DHEA and sex steroids, but not mouse glucocorticoids and mineralocorticoids, requires P450c17, which catalyzes both 17␣-hydroxylase and 17,20-lyase activities. We hypothesized that P450c17-knockout mice would have disordered sex steroid synthesis and disordered brain DHEA production and thus provide phenotypic clues about the functions of DHEA in mouse brain development. We deleted the mouse P450c17 gene in 127/SvJ mice and obtained several lines of mice from two lines of targeted embryonic stem cells. Heterozygotes were phenotypically and reproductively normal, but in all mouse lines, P450c17 ؊/؊ zygotes died by embryonic day 7, prior to gastrulation. The cause of this early lethality is unknown, as there is no known function of fetal steroids at embryonic day 7. Immunocytochemistry identified P450c17 in embryonic endoderm in E7 wild-type and heterozygous embryos, but its function in these cells is unknown. Enzyme assays of wild-type embryos showed a rapid rise in 17-hydroxylase activity between E6 and E7 and the presence of C 17,20 -lyase activity at E7. Treatment of pregnant females with subcutaneous pellets releasing DHEA or 17-OH pregnenolone at a constant rate failed to rescue P450c17 ؊/؊ fetuses. Treatment of normal pregnant females with pellets releasing pregnenolone or progesterone did not cause fetal demise. These data suggest that steroid products of P450c17 have heretofore-unknown essential functions in early embryonic mouse development.

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Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system

Cited by 128 publications

References 0 publications

Hypothalamic pituitary adrenal axis

Hypothalamic pituitary adrenal axis

Neurosteroid regulation of central nervous system development

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

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