α1-Adrenergic Receptors Regulate Neurogenesis and Gliogenesis

  1. Manveen K. Gupta,
  2. Robert S. Papay,
  3. Chris W. D. Jurgens,
  4. Robert J. Gaivin,
  5. Ting Shi,
  6. Van A. Doze and
  7. Dianne M. Perez
  1. Department of Molecular Cardiology, NB50, the Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, Ohio (M.K.G., R.S.P., R.J.G., T.S., D.M.P.); and Department of Pharmacology, Physiology, & Therapeutics, University of North Dakota, School of Medicine & Health Sciences, Grand Forks, North Dakota (C.W.D.J., V.A.D.)
  1. Address correspondence to:
    Dr. Dianne M. Perez, NB50, 9500 Euclid Avenue, The Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail: perezd{at}ccf.org

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

  • ↵1 After the α1C-AR was reclassified as the α1A-AR, the α1C-AR designation is no longer used.

  • 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].

  • 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.
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  1. Published online before print June 1, 2009, doi: 10.1124/mol.109.057307 Molecular Pharmacology August 2009 vol. 76 no. 2 314-326
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