A CONVERGENCE OF EXTRINSIC AND INTRINSIC SIGNALS FOR POSTMITOTIC DIFFERENTIATION OF NOCICEPTORS
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Diverse neuronal subtypes are the building blocks of functional neural circuits that underlie behaviors. The generation of correct types of neurons at appropriate times and positions is therefore fundamental to the development of the nervous system. Specification of neuronal subtypes is a multistep process that extends beyond the initial specification of neural progenitors and continues as postmitotic neurons differentiate further. The postmitotic aspect of neuronal subtype specification, although important for generation of neuronal subtype diversity, remains understudied. Here, using nociceptors, a class of primary sensory neurons in the dorsal root ganglion (DRG) that detect painful stimuli, as a model system and a combination of in vivo and in vitro approaches, we uncover a novel mechanism by which NGF, the prototypic neurotrophic factor and Runx1, a Runx family transcription factor, coordinate the specification of nonpeptidergic nociceptors, a major, well-characterized nociceptor subtype. We show that NGF promotes Runx1-dependent transcription that confers molecular and morphological identity of nonpeptidergic nociceptors through transcriptional upregulation of Cbfb. The protein product of Cbfb, CBFβ, is an integral component of the heterodimeric Runx1/CBFβ complex in DRGs, since conditional deletion of Cbfb in DRGs produces the same spectrum of phenotypes in nonpeptidergic nociceptors as observed in Runx1 mutants. NGF is necessary for Cbfb expression prior to the onset of NGF dependence of Runx1, implicating CBFβ as a critical link between NGF signaling and Runx1 function. NGF activates Cbfb expression through a MEK/ERK pathway. On the other hand, transcriptional initiation of Runx1 requires Islet1, a LIM-homeodomain transcription factor, while Cbfb expression is largely Islet1-independent. These findings together reveal a novel NGF/TrkA–MEK/ERK–Runx1/CBFβ axis that promotes gene expression and maturation of nonpeptidergic nociceptors and provide a common principle by which a convergence of extrinsic and intrinsic signals instructs postmitotic neuronal subtype specification.