title: Extrinsic and intrinsic signals converge on the Runx1/CBFβ transcription factor for nonpeptidergic nociceptor maturation.
abstract: The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFβ holocomplex is crucial for NGF-dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors. In contrast, transcriptional initiation of Runx1 in nonpeptidergic nociceptor precursors is dependent on the homeodomain transcription factor Islet1, which is largely dispensable for Cbfb expression. Thus, an NGF/TrkA-MAPK-CBFβ pathway converges with Islet1-Runx1 signaling to promote Runx1/CBFβ holocomplex formation and nonpeptidergic nociceptor maturation. Convergence of extrinsic and intrinsic signals to control heterodimeric transcription factor complex formation provides a robust mechanism for postmitotic neuronal subtype specification.
authors.affiliation: Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States.|Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States.
authors.forename: Siyi
authors.initials: S
authors.lastname: Huang
authors.affiliation: Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: O'Donovan
authors.affiliation: Seattle Children's Hospital, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Turner
authors.affiliation: Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States.|Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Ginty
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism*; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism; D009619:Nociceptors / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C493693:Cbfb protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C493726:Runx1 protein, mouse; D020932:Nerve Growth Factor
keywords: NGF; Runx1/CBFB; convergence of extrinsic and intrinsic factors; developmental biology; mouse; neuroscience; nociceptor differentiation; stem cells