Abstract
The understanding of the function of α1-adrenergic receptors in the brain has been limited due to a lack of specific ligands and antibodies. We circumvented this problem by using transgenic mice engineered to overexpress either wild-type receptor tagged with enhanced green fluorescent protein or constitutively active mutant α1-adrenergic receptor subtypes in tissues in which they are normally expressed. We identified intriguing α1A-adrenergic receptor subtype-expressing cells with a migratory morphology in the adult subventricular zone that coexpressed markers of neural stem cell and/or progenitors. Incorporation of 5-bromo-2-deoxyuridine in vivo increased in neurogenic areas in adult α1A-adrenergic receptor transgenic mice or normal mice given the α1A-adrenergic receptor-selective agonist, cirazoline. Neonatal neurospheres isolated from normal mice expressed a mixture of α1-adrenergic receptor subtypes, and stimulation of these receptors resulted in increased expression of the α1B-adrenergic receptor subtype, proneural basic helix-loop-helix transcription factors, and the differentiation and migration of neuronal progenitors for catecholaminergic neurons and interneurons. α1-Adrenergic receptor stimulation increased the apoptosis of astrocytes and regulated survival of neonatal neurons through phosphatidylinositol 3-kinase signaling. However, in adult normal neurospheres, α1-adrenergic receptor stimulation increased the expression of glial markers at the expense of neuronal differentiation. In vivo, S100-positive glial and βIII tubulin neuronal progenitors colocalized with either α1-adrenergic receptor subtype in the olfactory bulb. Our results indicate that α1-adrenergic receptors can regulate both neurogenesis and gliogenesis that may be developmentally dependent. Our findings may lead to new therapies to treat neurodegenerative diseases.
Footnotes
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↵1 After the α1C-AR was reclassified as the α1A-AR, the α1C-AR designation is no longer used.
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This study was supported by the National Institutes of Health Heart, Lung, and Blood Institute [Grant 5-R01-HL61438]; National Institutes of Health National Center for Research Resources INBRE Program [Grant P20-RR016741]; National Science Foundation, Faculty Early Career Development Award [Grant 0347259]; and National Science Foundation, Major Research Instrumentation Award [Grant 0619688].
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ABBREVIATIONS: SVZ, subventricular zone; AR, adrenergic receptor; bHLH, basic helix-loop-helix; BrdU, 5-bromo-2′-deoxyuridine; CAM, constitutively active mutant; EGF, epidermal growth factor; EGFP, enhanced green fluorescence protein; FBS, fetal bovine serum; FGF, fibroblast growth factor; NSC, neural stem cell; PBS, phosphate-buffered saline; RMS, rostral migratory stream; RT, room temperature; SGZ, subgranular zone; TAP, transient amplifying progenitor; TUNEL, terminal deoxynucleotidyl transferase; VEGF, vascular endothelial growth factor; GFAP, glial fibrillary acidic protein; KO, knockout; DMEM, Dulbecco's modified Eagle's medium; FACS, fluorescence-activated cell sorting; NMDA, N-methyl-d-aspartate; PKC, protein kinase C; PCR, polymerase chain reaction; MAP2, microtubule-associated protein-2; D-PBS, Dulbecco's phosphate-buffered saline; PD98059, 2′-amino-3′-methoxyflavone; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SP600125, anthra[1-9-cd]pyrazol-6(2H)-one; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; Go6983, 3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione; ICI-118,551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol.
- Accepted June 1, 2009.
- Received April 28, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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