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Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation.

ABSTRACT: The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes.

SUBMITTER: Dykes IM

PROVIDER: S-EPMC2829025 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation.

Dykes Iain M IM Lanier Jason J Eng S Raisa SR Turner Eric E EE

Neural development 20100122

The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of th ...[more]

PMID: 20096094

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Project description:BackgroundWhile the transcriptional code governing retinal ganglion cell (RGC) type specification begins to be understood, its interplay with neurotrophic signaling is largely unexplored. In mice, the transcription factor Brn3a/Pou4f1 is expressed in most RGCs, and is required for the specification of RGCs with small dendritic arbors. The Glial Derived Neurotrophic Factor (GDNF) receptor Ret is expressed in a subset of RGCs, including some expressing Brn3a, but its role in RGC development is not defined.MethodsHere we use combinatorial genetic experiments using conditional knock-in reporter alleles at the Brn3a and Ret loci, in combination with retina- or Ret specific Cre drivers, to generate complete or mosaic genetic ablations of either Brn3a or Ret in RGCs. We then use sparse labelling to investigate Brn3a and Ret gene dosage effects on RGC dendritic arbor morphology. In addition, we use immunostaining and/or gene expression profiling by RNASeq to identify transcriptional targets relevant for the potential Brn3a-Ret interaction in RGC development.ResultsWe find that mosaic gene dosage manipulation of the transcription factor Brn3a/Pou4f1 in neurotrophic receptor Ret heterozygote RGCs results in altered cell fate decisions and/or morphological dendritic defects. Specific RGC types are lost if Brn3a is ablated during embryogenesis and only mildly affected by postnatal Brn3a ablation. Sparse but not complete Brn3a heterozygosity combined with complete Ret heterozygosity has striking effects on RGC type distribution. Brn3a only mildly modulates Ret transcription, while Ret knockouts exhibit slightly skewed Brn3a and Brn3b expression during development that is corrected by adult age. Brn3a loss of function modestly but significantly affects distribution of Ret co-receptors GFRα1-3, and neurotrophin receptors TrkA and TrkC in RGCs.ConclusionsBased on these observations, we propose that Brn3a and Ret converge onto developmental pathways that control RGC type specification, potentially through a competitive mechanism requiring signaling from the surrounding tissue.

Project description:Pain is a common symptom associated with disorders involving the orofacial structures. Most acute orofacial painful conditions are easily recognized, but the pharmacological treatment may be limited by the adverse events of current available drugs and/or patients’ characteristics. In addition, chronic orofacial pain conditions represent clinical challenges both, in terms of diagnostic and treatment. There is growing evidence that specialized pro-resolution lipid mediators (SPMs) present potent analgesic effects, in addition to their well characterized role in the resolution of inflammation. Maresins (MaR-1 and MaR-2) were the last described members of this family, and MaR-2 analgesic action has not yet been reported. Herein the effect of MaR-2 in different orofacial pain models was investigated. MaR-2 (1 or 10 ng) was always delivered via medullary subarachnoid injection, which corresponds to the intrathecal treatment. A single injection of MaR-2 caused a significant reduction of phases I and II of the orofacial formalin test in rats. Repeated injections of MaR-2 prevented the development of facial heat and mechanical hyperalgesia in a model of post-operative pain in rats. In a model of trigeminal neuropathic pain (CCI-ION), repeated MaR-2 injections reversed facial heat and mechanical hyperalgesia in rats and mice. CCI-ION increased c-Fos positive neurons and CGRP+ activated (nuclear pNFkB) neurons in the trigeminal ganglion (TG), which were restored to sham levels by MaR-2 repeated treatment. In conclusion, MaR-2 showed potent and long-lasting analgesic effects in inflammatory and neuropathic pain of orofacial origin and the inhibition of CGRP-positive neurons in the TG may account for MaR-2 action. Graphical abstract Image 1 Highlights • MaR-2 reduces formalin-induced nociceptive behavior.• MaR-2 prevents heat and mechanical hyperalgesia in the postoperative pain model.• MaR-2 reverses heat and mechanical hyperalgesia in a neuropathic pain model.• MaR-2 reduces c-Fos activation in the trigeminal ganglion.• MaR-2 reduces the activation of CGRP+ neurons in the trigeminal ganglion.

Dataset Information

Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation.

Publications

Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation.

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