1. The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception
- Author
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Eric Bellefroid, Claude Van Campenhout, Calvin Leung, Anton A. Polyansky, Arabella Meixner, Vanja Nagy, Tiffany Cole, Thang M Khoung, Ivona Kozieradzki, Domagoj Cikes, Josef M. Penninger, Simon Vermeiren, Daniel Wenzel, Maria Novatchkova, and G. Gregory Neely
- Subjects
Male ,Sensory Receptor Cells ,Neurogenesis ,Molecular Sequence Data ,Xenopus ,Nerve Tissue Proteins ,Sensory system ,Crystallography, X-Ray ,Xenopus laevis ,Report ,Hereditary sensory and autonomic neuropathy ,medicine ,Animals ,Humans ,Cell Lineage ,Amino Acid Sequence ,Hereditary Sensory and Autonomic Neuropathies ,Molecular Biology ,Transcription factor ,Neurons ,Regulation of gene expression ,Sequence Homology, Amino Acid ,biology ,Gene Expression Profiling ,Pain Perception ,Cell Biology ,Anatomy ,Fibroblasts ,biology.organism_classification ,medicine.disease ,Immunohistochemistry ,Sensory neuron ,Protein Structure, Tertiary ,Cell biology ,HEK293 Cells ,medicine.anatomical_structure ,Nociception ,Gene Expression Regulation ,Mutation ,Drosophila ,Female ,Carrier Proteins ,Corrigendum ,Developmental Biology - Abstract
PR homology domain-containing member 12 (PRDM12) belongs to a family of conserved transcription factors implicated in cell fate decisions. Here we show that PRDM12 is a key regulator of sensory neuronal specification in Xenopus. Modeling of human PRDM12 mutations that cause hereditary sensory and autonomic neuropathy (HSAN) revealed remarkable conservation of the mutated residues in evolution. Expression of wild-type human PRDM12 in Xenopus induced the expression of sensory neuronal markers, which was reduced using various human PRDM12 mutants. In Drosophila, we identified Hamlet as the functional PRDM12 homolog that controls nociceptive behavior in sensory neurons. Furthermore, expression analysis of human patient fibroblasts with PRDM12 mutations uncovered possible downstream target genes. Knockdown of several of these target genes including thyrotropin-releasing hormone degrading enzyme (TRHDE) in Drosophila sensory neurons resulted in altered cellular morphology and impaired nociception. These data show that PRDM12 and its functional fly homolog Hamlet are evolutionary conserved master regulators of sensory neuronal specification and play a critical role in pain perception. Our data also uncover novel pathways in multiple species that regulate evolutionary conserved nociception.
- Published
- 2015