alpha1-Adrenergic receptors regulate neurogenesis and gliogenesis.
The understanding of the function of alpha(1)-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 alpha(1)-adrenergic receptor subtypes in tissues in which they are normally expressed. We identified intriguing alpha(1A)-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 alpha(1A)-adrenergic receptor transgenic mice or normal mice given the alpha(1A)-adrenergic receptor-selective agonist, cirazoline. Neonatal neurospheres isolated from normal mice expressed a mixture of alpha(1)-adrenergic receptor subtypes, and stimulation of these receptors resulted in increased expression of the alpha(1B)-adrenergic receptor subtype, proneural basic helix-loop-helix transcription factors, and the differentiation and migration of neuronal progenitors for catecholaminergic neurons and interneurons. alpha(1)-Adrenergic receptor stimulation increased the apoptosis of astrocytes and regulated survival of neonatal neurons through phosphatidylinositol 3-kinase signaling. However, in adult normal neurospheres, alpha(1)-adrenergic receptor stimulation increased the expression of glial markers at the expense of neuronal differentiation. In vivo, S100-positive glial and betaIII tubulin neuronal progenitors colocalized with either alpha(1)-adrenergic receptor subtype in the olfactory bulb. Our results indicate that alpha(1)-adrenergic receptors can regulate both neurogenesis and gliogenesis that may be developmentally dependent. Our findings may lead to new therapies to treat neurodegenerative diseases.
Gupta
Manveen K
MK
Department of Molecular Cardiology, NB50, the Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Papay
Robert S
RS
Jurgens
Chris W D
CW
Gaivin
Robert J
RJ
Shi
Ting
T
Doze
Van A
VA
Perez
Dianne M
DM
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism
D058646:Adrenergic alpha-1 Receptor Agonists; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D049452:Green Fluorescent Proteins; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D018340:Receptors, Adrenergic, alpha-1; C547714:Adra1a protein, mouse; C014282:cirazoline