Tyrosine hydroxylase (EC 1.14.16.2 ) is involved in the conversion of phenylalanine to dopamine. As the rate-limiting
enzyme in the synthesis of catecholamines, tyrosine hydroxylase has a key role in the physiology of adrenergic neurons.
NCBI Summary:
The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]
General function
Enzyme, Oxidoreductase
Comment
Follicular fluid norepinephrine and dopamine concentrations are higher in polycystic ovary syndrome. Musalı N et al. (2016) The aim of the present study was to compare follicular fluid (FF) levels of norepinephrine (NE) and dopamine (DA) in polycystic ovary syndrome (PCOS) and non-PCOS patients who underwent in vitro fertilization (IVF). Forty-seven PCOS patients (study group) and 61 patients with male factor infertility (control group) who underwent IVF using GnRH agonist protocol were recruited. Concentrations of NE and DA were measured in FF specimens of all patients. Demographic characteristics were comparable between the groups. Significantly higher levels of NE were measured in FF of PCOS patients (median: 61.05 nmol/l) compared to those with male infertility (median: 49.82 nmol/l). Similarly, significantly higher levels of DA were measured in FF of PCOS patients (median: 23.70 nmol/l) compared to those with male infertility (median: 18.28 nmol/l). In conclusion, the FF concentrations of both catecholamine are increased in PCOS patients when compared to non-PCOS patients.//////////////////
Cellular localization
Cytoplasmic
Comment
Ovarian function
Steroid metabolism
Comment
An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Lara HE 2000 et al.
A form of polycystic ovary (PCO) resembling some aspects of the human PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was carried out to test the hypotheses that this change in sympathetic tone is related to an augmented production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons, including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These functional changes were accompanied by restoration of the number of antral follicles per ovary that had been depleted by EV and a significant reduction in the number of both precystic follicles and follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology and/or maintenance of the PCO syndrome in humans.
/////////////////////////
Multiple roles for dopamine in Drosophila development. Neckameyer WS et al. Manipulation of dopamine levels by inhibition of tyrosine hydroxylase activity was accomplished in Drosophila melanogaster larval instars by feeding enzyme inhibitors for a 24-hr period. Behavioral assays performed immediately after treatment demonstrated that larval phototaxis, salt aversion, and heptanol preference were unaffected by reduced levels of dopamine. Within a few hours of treatment, the larvae ceased exploratory behavior and were unresponsive to external stimuli; these larvae eventually died. This behavior is strikingly similar to that displayed by dopamine-deficient transgenic mice. Treated larvae placed immediately onto normal food (to replenish dopamine levels) showed significant developmental delays and decreased fertility as adults. The lethality, developmental retardation, and decrease in fertility were reversed by addition of L-DOPA to inhibitor-containing food, suggesting that these effects were due solely to inhibition of tyrosine hydroxylation. Depletion of dopamine in newly eclosed females resulted in abnormally developed ovaries. These results suggest that the enzymatic function of tyrosine hydroxylase is vital and that reduced levels of dopamine result in akinesia and lethality, developmental retardation, and decreased fertility.
Expression regulated by
Comment
Ovarian localization
neurons
Comment
Mayerhofer A, reported that intraovarian neurons contain tyrosine hydroxylase (TH), the
rate-limiting enzyme in catecholamine biosynthesis. They showed that the primate ovary expresses both the
genes encoding TH and dopamine beta-hydroxylase (DBH), the key enzymes in
norepinephrine (NE) biosynthesis. Ovarian neurons were identified as a site of
TH and DBH gene expression, and oocytes were identified as an
exclusive site of DBH synthesis.
Origin and Ontogeny of Mammalian Ovarian Neurons. Les Dees W et al. Mammalian ovaries contain sympathetic neurons expressing the low affinity neurotropin receptor (p75(NTR)). To date neither the role these neurons might play in ovarian physiology nor their embryological origin is known. Immunohistochemistry was used to detect postnatal changes in distribution and number of both p75(NTR)-positive and tyrosine hydroxylase (TH)-positive neurons in rhesus monkey ovaries. Pig fetuses were used to map the pathway of ovarian neuronal migration during embryonic development. Antiserum to p75(NTR) revealed the presence of isolated neurons and neurons clustered into ganglia in 2 month old monkey ovaries. After 8 months, the neurons exhibited well-developed processes, and other than being more extensively interlaced, the localization and morphology did not change after 2 yr of age. Total number of p75(NTR)-positive neurons present decreased gradually between 2 months and 12 yr of age and declined markedly with reproductive aging. Conversely, subpopulation of neurons immunoreactive to anti-TH increased significantly at puberty, then declined with the loss of reproductive capacity. By day 21 of fetal life in the pig, p75(NTR) neurons had migrated medially from the neural crest to form the para-aortic autonomic ganglia. Some neurons migrated ventrally from the ganglia, then continued ventro-laterally to enter the genital ridge. By day 27, neurons had entered the developing ovary, and by day 35, the migration was complete with neurons demonstrating immunoreactivity to NeuN, a neuron-specific marker. Results demonstrate that p75(NTR -) expressing ovarian neurons originate from the neural crest and that a catecholaminergic subset is associated with pubertal maturation of the ovary and subsequent reproductive function.
Follicle stages
Primordial
Comment
Ovarian innervation develops before initiation of folliculogenesis in the rat. Malamed S 1992 et al.
Sympathetic neurotransmitters have been shown to be present in the ovary of the rat during early postnatal development and to affect steroidogenesis before the ovary becomes responsive to gonadotropins, and before the first primordial follicles are formed. This study was undertaken to determine if development of the ovarian innervation is an event that antedates the initiation of folliculogenesis in the rat, Rattus norvegicus. Serial sections of postnatal ovaries revealed a negligible frequency of follicles 24 h after birth (about 1 primordial follicle per ovary). Twelve hours later there were about 500 follicles per ovary, a number that more than doubled to about 1300 during the subsequent 12 h, indicating that an explosive period of follicular differentiation occurs between the end of postnatal days 1 and 2. Electron microscopy demonstrated that before birth the ovaries are already innervated by fibers containing clear and dense-core vesicles. Immunohistochemistry performed on either fetal (day 19) or newborn (less than 15h after birth) ovaries showed the presence of catecholaminergic nerves, identified by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. While some of these fibers innervate blood vessels, others are associated with primordial ovarian cells, thereby suggesting their participation in non-vascular functions. Since prefollicular ovaries are insensitive to gonadotropins, the results suggest that the developing ovary becomes subjected to direct neurogenic influences before it acquires responsiveness to gonadotropins.
/////////////////////////The primate ovary contains a population of catecholaminergic neuron-like cells expressing nerve growth factor receptors. Dees WL 1995 et al.
The ovary of humans and nonhuman primates is innervated by sympathetic and sensory neurons of the peripheral nervous system. Recent studies demonstrated that the density of the sympathetic innervation to the rhesus monkey ovary is developmentally regulated, with adult density being attained around the time of puberty. In the present study, we used an immunocytochemical approach to obtain insights into the cell-cell signaling mechanisms that may contribute to the functional maintenance of this innervation. Because sympathetic neurons of the peripheral nervous system require target-derived neurotropins for their survival and function, experiments were conducted to determine if one of the receptors recognized by neurotropins is expressed in fibers innervating the primate ovary. A monoclonal antibody to the human low-affinity nerve growth factor (NGF) receptor, termed p75 NGFR because of its molecular weight, demonstrated the presence of this receptor in nerve fibers innervating the ovarian vasculature, interstitial tissue, and developing follicles of the gland. In addition, as shown in rodents, p75 NGFR immunoreactivity was detected in nonneuronal, endocrine cells of the ovary, specifically the thecal cell layer of developing follicles. Unexpectedly, however, the monkey ovary was also found to contain a network of small p75 NGFR immunoreactive cells distributed throughout the ovarian medulla and cortex. These cells, identified as such by confocal microscopy, had a neural-like appearance and displayed both neurofilament and neuron-specific enolase immunoreactivity. They appeared to be densely interconnected and were seen innervating the ovarian vasculature, the thecal cell layer of follicles, and, occasionally, primordial follicles. Double immunohistochemical procedures demonstrated that a subpopulation of these intraovarian, p75 NGFR-bearing neuron-like cells are catecholaminergic, as determined by their immunoreactivity to antibodies to tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. RNA blot hybridization revealed the presence of p75 NGFR messenger RNA in the monkey ovary, thus demonstrating the ability of the gland to synthesize the receptors. These results demonstrate that the primate ovary contains an intrinsic network of neuron-like cells. Because such a neuronal network has not been detected in rodents or other non-primate species, it would appear that its presence in the primate ovary may have evolutionary significance.
/////////////////////////