Small-molecule activation of neuronal cell fate.
We probed an epigenetic regulatory path from small molecule to neuronal gene activation. Isoxazole small molecules triggered robust neuronal differentiation in adult neural stem cells, rapidly signaling to the neuronal genome via Ca(2+) influx. Ca(2+)-activated CaMK phosphorylated and mediated nuclear export of the MEF2 regulator HDAC5, thereby de-repressing neuronal genes. These results provide new tools to explore the epigenetic signaling circuitry specifying neuronal cell fate and new leads for neuro-regenerative drugs.
Schneider
Jay W
JW
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Gao
Zhengliang
Z
Li
Shijie
S
Farooqi
Midhat
M
Tang
Tie-Shan
TS
Bezprozvanny
Ilya
I
Frantz
Doug E
DE
Hsieh
Jenny
J
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D051792:Basic Helix-Loop-Helix Proteins; D007555:Isoxazoles; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D054852:Small Molecule Libraries; C093564:Neurogenic differentiation factor 1; C104722:glutamate receptor ionotropic, AMPA 2