Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP.
Extracellular signals and cell-intrinsic transcription factors cooperatively instruct generation of diverse neurons. However, little is known about how neural progenitors integrate both cues and orchestrate chromatin changes for neuronal specification. Here, we report that extrinsic signal retinoic acid (RA) and intrinsic transcription factor Neurogenin2 (Ngn2) collaboratively trigger transcriptionally active chromatin in spinal motor neuron genes during development. Retinoic acid receptor (RAR) binds Ngn2 and is thereby recruited to motor neuron genes targeted by Ngn2. RA then facilitates the recruitment of a histone acetyltransferase CBP to the Ngn2/RAR-complex, markedly inducing histone H3/H4-acetylation. Correspondingly, timely inactivation of CBP and its paralog p300 results in profound defects in motor neuron specification and motor axonal projection, accompanied by significantly reduced histone H3-acetylation of the motor neuron enhancer. Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell fate specification through their synergistic activity to trigger transcriptionally active chromatin.
Lee
Seunghee
S
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lee
Bora
B
Lee
Jae W
JW
Lee
Soo-Kyung
SK
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002843:Chromatin / Q000502:physiology*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D014157:Transcription Factors; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D014212:Tretinoin; D014404:Tubulin; D050880:p300-CBP Transcription Factors; C577484:NES protein, human; C577485:Nes protein, mouse; C102938:Neurog2 protein, mouse; C498709:Pag1 protein, mouse; C462941:beta3 tubulin, mouse; C063843:insulin gene enhancer binding protein Isl-1