Age‐associated changes in mRNA levels of Phox2, norepinephrine transporter and dopamine β‐hydroxylase in the locus coeruleus and adrenal glands of rats

Zhu, Meng-Yang; Wang, Weiping; Iyo, Abiye H.; Ordway, Gregory A.; Kim, Kwangsoo

doi:10.1111/j.1471-4159.2005.03245.x

Cited by 18 publications

(22 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results suggest that NET might contribute to the decrease in myocardial β 1 -AR mRNA with aging. The NET change appears accordant with previous observations (Shores et al, 1999;Zhu et al, 2005), which showed that NET mRNA expression in locus coeruleus (LC) was significantly decreased with aging in rats, and the level of NET in the LC of 23-month-old rats showed less than half of that found in the 1-month-old rats (Zhu et al, 2005). These previous findings also indicate that there was an age-dependent decrease in myocardial NET binding sites by 36% in elderly patients [(60±3) years] without apparent heart failure, and NET activity was ~50% lower than that in children [(14±3) years] (Leineweber et al, 2002).…”

Section: Discussionsupporting

confidence: 92%

Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

et al. 2009

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

Evidence suggests that the deterioration of communication between the sympathetic nervous system and cardiovascular system always accompanies the aging of human and animals. Cardiac sympathetic norepinephrine (NE) transporter (NET) on presynaptic membrane is a predominant component to eliminate released NE in the synaptic cleft and maintains the sensitivity of the β-adrenergic receptor (β-AR). In the present study, we investigated NET and β 1 -AR mRNA levels and sympathetic nerve density in cardiac sympathetic ganglion and left ventricular myocardium in 2-and 16-month-old rats with Northern blot analysis and immunohistochemistry. The expression levels of NET mRNA, NET protein and β 1 -AR mRNA in the ganglia or myocardia of 16-month-old rats were markedly reduced by 67%, 26%, and 43%, respectively, in comparison with those in 2-month-old rats. Our results also show that aging induces a strong decrease of the catecholaminergic nerve fiber density.

show abstract

Section: Discussionsupporting

confidence: 92%

Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

et al. 2009

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

show abstract

“…These studies indicate that Phox2a/2b may participate in direct transcriptional activation of DBH and NET genes in vitro . Our study showed that a significant reduction in mRNAs of Phox2 in the LC and adrenal glands of aging rats was accompanied by a decline in mRNA levels of NET and DBH (Zhu et al. 2005), suggesting a possible relationship between Phox2 genes and these marker genes in noradrenergic neurons after birth.…”

mentioning

confidence: 60%

Effects of transcription factors Phox2 on expression of norepinephrine transporter and dopamine β‐hydroxylase in SK‐N‐BE(2)C cells

Fan

Huang

Kieran

et al. 2009

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

The norepinephrine (NE) transporter (NET) is located presynaptically on noradrenergic nerve terminals. Reuptake of synaptically released NE by NETs is the major physiological mechanism by which released NE is inactivated (Barker and Blakely 1995). In the rat brain NET expression is restricted to noradrenergic neurons (Lorang et al. 1994;Comer et al. 1998;Schroeter et al. 2000) and has not been found in the serotonergic, dopaminergic, or adrenergic neurons. This unique distribution indicates that NET is essential for phenotypic specification and is a hallmark protein of noradrenergic neurons. Dopamine b-hydroxylase (DBH, EC 1.14.2.1) is another hallmark protein of noradrenergic neurons ) because of its specific activity to catalyze the conversion of dopamine to form NE (Kaufman and Friedman 1965) and its highly restricted expression pattern in noradrenergic neurons. In most cases, NET and DBH are co-expressed in noradrenergic neurons of These authors contributed equally to this work. Abbreviations used: DBH, dopamine b-hydroxylase; HD, homeodomain; KRH, Krebs-Ringer-HEPES; LC, locus coeruleus; NE, norepinephrine; NET, NE transporter; shRNA, short hairpin RNAs; TH, tyrosine hydroxylase. AbstractPhox2a and Phox2b are two homeodomain proteins that control the differentiation of noradrenergic neurons during embryogenesis. In the present study, we examined the possible effect of Phox2a/2b on the in vitro expression of the norepinephrine transporter (NET) and dopamine b-hydroxylase (DBH), two important markers of the noradrenergic system. SK-N-BE(2)C cells were transfected with cDNAs or short hairpin RNAs specific to the human Phox2a and Phox2b genes. Transfection of 0.1 to 5 lg of cDNAs of Phox2a or Phox2b significantly increased mRNA and protein levels of NET and DBH in a concentration-dependent manner. As a consequence of the enhanced expression of NET after transfection, there was a parallel increase in the uptake of [ CNS and PNS (Lorang et al. 1994;Schroeter et al. 2000). Therefore, as the hallmarks of noradrenergic circuit, the expression of NET and DBH has been tightly bound to the generation and function of noradrenergic neurons in vitro and in vivo.Since the last decade, substantial progress has been made in uncovering critical extracellular signals and transcriptional regulators that control the specification and differentiation of catecholaminergic neurons. Among them, Phox2a and Phox2b, two closely related homeodomain (HD) transcription factors with similar expression patterns, are pivotal for the development of noradrenergic neurons throughout the nervous system during embryogenesis Hirsch et al. 1998;Pattyn et al. 2000). For instance, inactivation of the Phox2a gene in mice leads to the agenesis of the locus coeruleus (LC) . The silencing of the Phox2b gene disrupts noradrenergic differentiation throughout the CNS and PNS (Pattyn et al. 1999(Pattyn et al. , 2000. Also, Phox2 genes are involved in the transcriptional control of the noradrenergic neurotransmitter phenotypes as they regulate the gene expre...

show abstract

“…(2) They are essential and determinant for the generation and development of noradrenergic neurons during embryogenesis; (3) Phox2a genes are commonly considered to be persistently present in adult brains; and (4) Phox2a/2b can directly transactivate the promoters of DBH and NET, both characteristic factors of noradrenergic neurons. Our previous study demonstrated that reduced Phox2 mRNA levels in the LC of aged rats was accompanied by parallel reduction of DBH and NET mRNA levels (Zhu et al, 2005), indicating the possibility of a causal relationship between Phox2 genes and expression of the noradrenergic phenotypes during aging. If so, then delivery of related transcription factors into the LC of brains to up-regulate the phenotype may be a strategy to arrest or counteract the neurodegenerative process in aging or degenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…However, whether these genes still have modulatory effects on noradrenergic neurons and phenotypes in adult brains has not been elucidated. Our previous in vivo study showed that a significant reduction in mRNAs of NET and DBH in the LC and adrenal glands of aging rats was paralleled with a decline in mRNA levels of Phox2 (Zhu et al, 2005), suggesting a possible relationship between these marker genes and Phox2 genes in noradrenergic neurons after birth. Furthermore, in vitro investigations (Yang et al, 1998, Stanke et al, 1999, Kim et al, 2002, Fan et al, 2009) demonstrated direct transcriptional activation of DBH and NET genes by Phox2 genes.…”

mentioning

confidence: 94%

Transcription factor Phox2 upregulates expression of norepinephrine transporter and dopamine β-hydroxylase in adult rat brains

Fan¹,

Huang²,

Duffourc³

et al. 2011

Neuroscience

View full text Add to dashboard Cite

Degeneration of the noradrenergic locus coeruleus (LC) in aging and neurodegenerative diseases is well documented. Slowing or reversing this effect may have therapeutic implications. Phox2a and Phox2b are homeodomain transcriptional factors that function as determinants of the noradrenergic phenotype during embryogenesis. In the present study, recombinant lentiviral eGFP-Phox2a and -Phox2b (vPhox2a and vPhox2b) were constructed to study the effects of Phox2a/2b over-expression on dopamine β-hydroxylase (DBH) and norepinephrine transporter (NET) levels in central noradrenergic neurons. Microinjection of vPhox2 into the LC of adult rats significantly increased Phox2 mRNA levels in the LC region. Over-expression of either Phox2a or Phox2b in the LC was paralleled by significant increases in mRNA and protein levels of DBH and NET in the LC. Similar increases in DBH and NET protein levels were observed in the hippocampus following vPhox2 microinjection. In the frontal cortex, only NET protein levels were significantly increased by vPhox2 microinjection. Over-expression of Phox2 genes resulted in a significant increase in BrdU-positive cells in the hippocampal dentate gyrus. The present study demonstrates an upregulatory effect of Phox2a and Phox2b on the expression of DBH and NET in noradrenergic neurons of rat brains, an effect not previously shown in adult animals. Phox2 genes may play an important role in maintaining the function of the noradrenergic neurons after birth, and regulation of Phox2 gene expression may have therapeutic utility in aging or disorders involving degeneration of noradrenergic neurons.

show abstract

Age‐associated changes in mRNA levels of Phox2, norepinephrine transporter and dopamine β‐hydroxylase in the locus coeruleus and adrenal glands of rats

Cited by 18 publications

References 65 publications

Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

Effects of transcription factors Phox2 on expression of norepinephrine transporter and dopamine β‐hydroxylase in SK‐N‐BE(2)C cells

Transcription factor Phox2 upregulates expression of norepinephrine transporter and dopamine β-hydroxylase in adult rat brains

Contact Info

Product

Resources

About