Extrinsic and intrinsic signals converge on the Runx1/CBFβ transcription factor for nonpeptidergic nociceptor maturation

  • Huang S
  • O'Donovan K
  • Turner E
  • et al.
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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.Animals detect and respond to their environment using their sensory nervous system, which forms through a complex, multi-step process. A precursor nerve cell’s fate is set early in its development, and determines the different nerve types it can become. As development progresses, sensory nerve cells develop further into distinct subtypes that perform particular tasks, such as responding to touch or pain.Nociceptors are the specialised sensory nerves that respond to potentially harmful stimuli. They form two distinct subtypes: peptidergic nerves detect potentially dangerous temperatures, whereas non-peptidergic nerves detect potentially dangerous mechanical sensations. Both subtypes originate from the same precursor nerve cell and both initially depend on an external molecule called NGF for their development and survival. During their development, non-peptidergic neurons stop responding to NGF and start producing a protein called Runx1, considered to be the ‘master regulator’ of non-peptidergic nerve cell development. Runx1 works by forming a complex with another protein called CBFbβ, and this complex activates a program of gene expression that is specific to non-peptidergic nerves. However it was unclear how an external signal, like NGF, can coordinate with or influence a nerve cell’s internal genetic program during the nerve’s development. It was also not known whether NGF and Runx1 interact with each other.By studying non-peptidergic nerve cell development in mice that lack NGF, Runx1 and other associated proteins, Huang et al. have now established the sequence of events that regulate the development of this nerve cell subtype. Two signalling pathways converge to switch on non-peptidergic nerve cell development. An NGF-driven signalling pathway activates the production of CBFβ, while another protein binds to the Runx1 gene to switch it on. This leads to the production of the Runx1 and CBFβ proteins that complex together to activate the non-peptidergic neuronal genetic program.These findings demonstrate how two different mechanisms converge to produce the component parts of a complex, which then activates a genetic program that drives the development of a particular neuronal subtype. Whether this mechanism is involved in determining the fate of other cell types remains a question for future work.

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Huang, S., O’Donovan, K. J., Turner, E. E., Zhong, J., & Ginty, D. D. (2015). Extrinsic and intrinsic signals converge on the Runx1/CBFβ transcription factor for nonpeptidergic nociceptor maturation. ELife, 4. https://doi.org/10.7554/elife.10874

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