Analysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues

Coker, George T.; Studelska, Dan; Harmon, Steve; Burke, William J.; O’Malley, Karen L.

doi:10.1016/0169-328x(90)90052-f

Cited by 83 publications

(40 citation statements)

References 26 publications

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“…Antisense RNA probe (100 pg) and sense RNA standards (0-80 pg) were derived from the human tyrosine hydroxylase clone phTH-63 (a generous gift of Karen O'Malley, Washington University). As reported (15), the HTH-1 and HTH-2 forms of tyrosine hydroxylase mRNA were present in roughly equimolar amounts in human substantia nigra. HTH-2 mRNA was densitometrically quantitated (because of better electrophoretic separation from undigested probe) although HTH-1 content appeared to change in parallel (data not shown).…”

mentioning

confidence: 63%

Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.

Bannon

Poosch

Xia

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

155

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The dopamine transporter is the primary means of inactivating synaptic dopamine as well as a major site of action for psychostimulants (such as cocaine and amphetamine) and for neurotoxins that induce parkinsonism. In the present study, a human dopamine transporter partial cDNA clone obtained by polymerase chain reaction exhibited 87% and 89% identity at the nucleic acid and amino acid levels, respectively, with transmembrane domains 3-5 of the rat homolog. This clone was used to quantitate human dopamine transporter mRNA by nuclease protection assay. The postmortem content of dopamine transporter mRNA in the substantia nigrae of 18-to 57-yr-old subjects was relatively constant, while in subjects >57 yr old, a precipitous (>95%) decline in substantia nigra dopamine transporter mRNA was evident. In contrast, tyrosine hydroxylase mRNA in the same samples declined in a linear manner with increasing age. In situ hybridization experiments confirmed the profound loss of dopamine transporter gene expression in melanin-positive (presumptive dopamine) nigral neurons. These data may begin to shed light on compensatory changes occurring in human dopamine neurons during normal aging.The actions of many neurotransmitters are terminated by rapid reuptake into presynaptic nerve endings via neurotransmitter-specific, high-affinity, Na+-dependent membrane transporter proteins. The transporter for the neurotransmitter dopamine (DA) is apparently the receptor through which psychostimulants such as cocaine and amphetamine exert their potent reinforcing properties, leading to psychostimulant abuse and dependence (1). In addition, the DA transporter mediates the active accumulation of neurotoxins such as 1-methyl-4-phenylpyridine into DA neurons (2, 3), resulting in DA cell death and a parkinsonian syndrome. Thus, understanding the regulation of human DA transporter gene expression is an important step toward elucidation of the molecular bases of psychostimulant drug abuse and of neurotoxin-induced (and quite possibly idiopathic) parkinsonism.Ligand binding to the human DA transporter decreases with age (4, 5), in keeping with other evidence for an age-related loss of DA neurons (6). Nevertheless, surprisingly little is known about the nature of normal age-related changes in human DA neurons, a process apparently distinct from the neuronal changes seen in Parkinson disease (6, 7). In the present study, a human DA transporter cDNA clone was obtained by polymerase chain reaction, exploiting predicted sequence homology with the recently cloned, functionally related human norepinephrine transporter (8). With the use of this clone, a precipitous, age-related loss of DA transporter mRNA was observed in human substantia nigra, while tyrosine hydroxylase mRNA, another phenotypic marker of DA neurons, decreased more linearly with age. These data may shed light on some compensatory changes occurring in human DA neurons during the normal aging process. MATERIALS AND METHODSHuman substantia nigrae used for biochemical analyses (n = 36) w...

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mentioning

confidence: 63%

Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.

Bannon

Poosch

Xia

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

155

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“…Interestingly, both negative cases were patients aged 50 years or older. It is therefore RT-PCR using primers spanning separate exons of the human tyrosine hydroxylase gene was performed on total RNA as described (23,36 Medical Sciences: Sorensen et al 5 possible that cases diagnosed as ONB in older patients represent yet another phenotypically neural tumor unrelated to pPNETs, and the two negative cases in the present study may be examples of this entity.…”

Section: Discussionmentioning

confidence: 99%

“…Oligonucleotide primers used for PCR included the FLIu-specific primer ESBP-2 (7), 11.3, which detects FLI1 and ERG sequences (5,11), and the EWS-specific primer ESBP-1 (7). RT-PCR detection of tyrosine hydroxylase expression was carried out using previously reported methods and primer pairs (23,36). Amplified products were analyzed by electrophoresis using 2% agarose gels and stained with ethidium bromide.…”

Section: Methodsmentioning

confidence: 99%

Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma.

Sorensen

Berean

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Olfactory neuroblastoma (ONB) is a malignant tumor of the nasal mucosa whose histogenesis is unclear. A relationship to neuroblastoma (NB), a pediatric tumor of the sympathetic nervous system, is based on morphologic similarities and the expression of similar neural antigens. However, the clinical presentation of ONB differs from that of NB, and MYCN amplification characteristic of NB is not observed. We have therefore examined the relationship of this malignancy to other classes of neural tumors. appear to act as aberrant transcription factors (10). Identification of EWS/FLI1 and EWS/ERG fusion transcripts by reverse transcription PCR (RT-PCR) has formed the basis of a sensitive and specific diagnostic test for pPNETs (11).Olfactory neuroblastoma (ONB) is a tumor of the nasal cavity that was first described in 1924 by Berger et al. (12). Since that time the histogenesis of this tumor has been vigorously debated, giving rise to a variety of other names, including esthesioneuroblastoma, olfactory neuroepithelioma, and others (13). A neural derivation is indicated ultrastructurally by the presence of dense core neurosecretory granules and neuritic processes within tumor cells and immunohistochemically by expression of neurofilament protein, neuron-specific enolase, and S-100 protein (14-17). Several anatomical origins of ONB have been suggested, including the sympathetic fibers of the anterior nasal cavity, the neuroectodermal cells of the olfactory placode, the sphenopalatine ganglion, and the organ of Jacobson (13). The proposed relationship to neuroblastoma (NB) implied in the name is based on morphologic similarities to primitive forms of NB, the identification of norepinephrine and dopamine ,B-hydroxylase (a key enzyme in the metabolic pathway of catecholamine synthesis) in a case of ONB (18), and a possible origin from sympathetic fibers of the nervus terminalis located in the anterior nasal cavity. Unlike NB, however, ONB rarely occurs in early childhood, tends to behave less aggressively than NB, and is rarely associated with catecholamine secretion (13,15). Moreover, the superior location of ONB within the nasal vault favors an origin from neuroectodermally derived cells of the olfactory placode. These clinicopathologic considerations have led to the alternative hypothesis that ONB is related to the pPNET family of primitive sarcomas.Although morphologically similar, a number of molecular features distinguish pPNETs and NBs. The t(11;22) and t(21;22) chromosomal translocations and gene fusions described for pPNETs have never been observed in NBs. Instead, these malignancies demonstrate amplification of the MYCN protooncogene in about 30% of the cases (19,20), and a similar proportion have allelic losses of the distal short arm of chromosome 1 (21,22). NBs are associated with catecholamine secretion, and expression of tyrosine hydroxylase, the ratelimiting enzyme in catecholamine biosynthesis, has been used diagnostically for the detection of residual NB cells (23

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“…With regard to the first issue, it is now generally appreciated that neither insulin nor leptin are synthesized to any significant degree in the adult brain. Although early studies using an immunoassay approach suggested that insulin might be synthesized in the developed (adult) brain (58), subsequent studies (30,52) suggest that, in fact, most if not all insulin that is found in the mature brain is transported there from the circulation after its release from the beta cells of the endocrine pancreas. A limitation to studies that have reported insulin synthesis within primary or transformed mammalian neuronal cell lines (36,112) based on the use of fetal or embryonic neurons, is that proteins are expressed in developing neurons with specific and differential time courses.…”

Section: Insulin and Leptin: Adiposity Signaling In The Cnsmentioning

confidence: 99%

Adiposity signals and food reward: expanding the CNS roles of insulin and leptin

Figlewicz

2003

American Journal of Physiology-Regulatory, Integrative and Comp

190

135

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Figlewicz, Dianne P. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 284: R882-R892, 2003;10.1152/ajpregu.00602.2002The hormones insulin and leptin have been proposed to act in the central nervous system (CNS) as adiposity signals as part of a theoretical negative feedback loop that senses the caloric stores of an animal and orchestrates adjustments in energy balance and food intake. Much research has provided support for both the existence of such a feedback loop and the specific roles that insulin and leptin may play. Most studies have focused on hypothalamic sites, which historically are implicated in the regulation of energy balance, and on the brain stem, which is a target for neural and humoral signals relating to ingestive acts. More recent lines of research, including studies from our lab, suggest that in addition to these CNS sites, brain reward circuitry may be a target for insulin and leptin action. These studies are reviewed together here with the goals of providing a historical overview of the findings that have substantiated the originally hypothesized negative feedback model and of opening up new lines of investigation that will build on these findings and allow further refinement of the model of adiposity signal/CNS feedback loop. The understanding of how motivational circuitry and its endocrine or neuroendocrine modulation contributes to normal energy balance regulation should expand possibilities for future therapeutic approaches to obesity and may lead to important insights into mental illnesses such as substance abuse or eating disorders. central nervous system; dopamine; food intake FROM HISTORICAL PERSPECTIVE TO MODERN PERSPECTIVEIn 1979, Porte, Woods, and colleagues (130) made the observation that putting a small amount of the metabolic hormone insulin directly into the cerebrospinal fluid (CSF) of nonhuman primates resulted in a significant decline in the animals' food intake and body weight. This observation was made in the context of ongoing studies in the field that suggested that a circulating humoral factor or factors could regulate both size of individual meals, as well as food intake and body weight, over a longer time course (31,83,90,117). In a subsequent review, Porte and Woods (94) proposed that insulin served as an "adiposity signal" whose levels in the brain reflected the size of adipose stores integrated over time and which served to complete a negative feedback loop that links the behavior of feeding with size of adipose stores, such that adipose mass remains fairly constant in adults over a relatively long time. Many studies over the intervening decades have essentially validated this basic concept (e.g., 3, 4, 15, 25, 84). In the mid-90s, a second candidate adiposity signal, Ob-protein or leptin, was identified (133), and the function of these two signals appears to be similar. A major research focus has been on the actions of these two hormones at the medial hypothalamus, which historically has be...

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Analysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues

Cited by 83 publications

References 26 publications

Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.

Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.

Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma.

Adiposity signals and food reward: expanding the CNS roles of insulin and leptin

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