Sequential RARbeta and alpha signalling in vivo can induce adult forebrain neural progenitor cells to differentiate into neurons through Shh and FGF signalling pathways.
We show here the role of retinoic acid receptor (RAR) beta and alpha signalling in proliferation and differentiation of endogenous adult forebrain neural progenitor cells (NPCs). RARbeta activation stimulates Sonic hedgehog signalling (Shh), and induces the proliferation of the NPCs. They can be induced to become Doublecortin (DCX) expressing migrating neuroblasts by RARalpha signalling, some of which differentiate into cholinergic neurons. The same signalling pathways cause the proliferation of embryonic forebrain NPCs. These cells express glial fibrillary acidic protein (GFAP) and are predominantly uni/bipolar, two characteristics of neuronal progenitor cells. We further show that fibroblast growth factor (FGF) signalling, induces the expression of the retinoic acid degrading enzyme cytochrome P450 (cyp) 26a1, and that one of its products, 4-oxo-RA, mimics the action of the RARalpha agonist in the differentiation of the NPCs into cholinergic neurons.
Goncalves
Maria Beatriz C V
MB
The Wolfson Centre For Age-Related Diseases, King's College London, Guy's Campus, London, UK.
Agudo
Marta
M
Connor
Siobhán
S
McMahon
Stephen
S
Minger
Stephen L
SL
Maden
Malcolm
M
Corcoran
Jonathan P T
JP
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology; D011758:Pyrroles / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014212:Tretinoin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D007093:Imidazoles; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D011758:Pyrroles; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C105686:SU 5402; C082925:retinoic acid receptor beta; C002202:4-oxoretinoic acid; D014212:Tretinoin; D005346:Fibroblast Growth Factors; C061121:liarozole