title: Genome-wide expression analysis of Ptf1a- and Ascl1-deficient mice reveals new markers for distinct dorsal horn interneuron populations contributing to nociceptive reflex plasticity.
abstract: Inhibitory interneurons of the spinal dorsal horn play critical roles in the processing of noxious and innocuous sensory information. They form a family of morphologically and functionally diverse neurons that likely fall into distinct subtypes. Traditional classifications rely mainly on differences in dendritic tree morphology and firing patterns. Although useful, these markers are not comprehensive and cannot be used to drive specific genetic manipulations targeted at defined subsets of neurons. Here, we have used genome-wide expression profiling of spinal dorsal horns of wild-type mice and of two strains of transcription factor-deficient mice (Ptf1a(-/-) and Ascl1/Mash1(-/-) mice) to identify new genetic markers for specific subsets of dorsal horn inhibitory interneurons. Ptf1a(-/-) mice lack all inhibitory interneurons in the dorsal horn, whereas only the late-born inhibitory interneurons are missing in Ascl1(-/-) mice. We found 30 genes that were significantly downregulated in the dorsal horn of Ptf1a(-/-) mice. Twenty-one of those also showed reduced expression in Ascl1(-/-) mice. In situ hybridization analyses of all 30 genes identified four genes with primarily non-overlapping expression patterns in the dorsal horn. Three genes, pDyn coding the neuropeptide dynorphin, Kcnip2 encoding a potassium channel associated protein, and the nuclear receptor encoding gene Rorb, were expressed in Ascl1-dependent subpopulations of the superficial dorsal horn. The fourth gene, Tfap2b, encoding a transcription factor, is expressed mainly in a Ascl1-independent subpopulation of the deep dorsal horn. Functional experiments in isolated spinal cords showed that the Ascl1-dependent inhibitory interneurons are key players of nociceptive reflex plasticity.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland. hwildner@pharma.uzh.ch
authors.forename: Hendrik
authors.initials: H
authors.lastname: Wildner
authors.forename: Rebecca
authors.initials: R
authors.lastname: Das Gupta
authors.forename: Dominique
authors.initials: D
authors.lastname: Bröhl
authors.forename: Paul A
authors.initials: PA
authors.lastname: Heppenstall
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D007395:Interneurons / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D059225:Nociception / Q000502:physiology*; D020671:Posterior Horn Cells / Q000378:metabolism*; D012018:Reflex / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C062602:transcription factor PTF1