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.
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Jay W
JW
Schneider
Zhengliang
Z
Gao
Shijie
S
Li
Midhat
M
Farooqi
Tie-Shan
TS
Tang
Ilya
I
Bezprozvanny
Doug E
DE
Frantz
Jenny
J
Hsieh
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