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Cell Cycle
2015 Jan 01;1412:1799-808. doi: 10.1080/15384101.2015.1036209.
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The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.
Nagy V, Cole T, Van Campenhout C, Khoung TM, Leung C, Vermeiren S, Novatchkova M, Wenzel D, Cikes D, Polyansky AA, Kozieradzki I, Meixner A, Bellefroid EJ, Neely GG, Penninger JM.
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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.
Figure 1. Prdm12 gain and loss of function affects expression of sensory neuronal markers in Xenopus. (A) Real-time qPCR analysis to assess the expression of the indicated genes in stage 28 animal cap explants isolated from Xenopus embryos injected with noggin mRNA, mouse Prdm12 mRNA and treated with retinoic acid (RA) as indicated. Expression levels (fold increase ± SD) were normalized to GAPDH and compared to the expression level of noggin-injected RA treated caps, which was arbitrarily defined as 1. (B) Lateral views of Xenopus tailbud or tadpole stage embryos injected unilaterally with Prdm12 antisense morpholinos (MO) and hybridized with the indicated antisense probes. The injected side is revealed by LacZ staining in blue. Note that all sensory markers tested are upregulated upon Prdm12 overexpression in caps, and in Prdm12 morphant embryos their expression is reduced in trigeminal and epibranchial placodes. (C) Sequence alignment of Homo sapiens (Hos) and Xenopus laevis (Xel) PRDM12 proteins. Orange and blue bars indicate the positions of the SET (PF00856) and ZnF_C2H2 (SM00355) domains, respectively. Conserved residues are boxed. Light blue boxes highlight Cys and His residues which bind the Zn ions. Residues found to be mutated in patients are highlighted with red background and red triangles. NCBI protein accessions NP_067632 and NP_001079854. Alignment was rendered using ESPript (PMID: 24753421 deciphering key features in protein structures with the new ENDscript server).
Figure 2. Human PRDM12 mutations cause structural instability and impair induction of sensory neuronal markers. (A) The structural modeling of the human PRDM12 mutations is based on the crystal structure of the human PRDM12 methyltransferase domain (PDB:3EP0). Mutated residues and the substitutions are colored in green and gray, respectively, and shown in stick representation. Protein is shown using cartoon and bonds representations. N- and C-terminal parts are colored in violet and cyan, respectively. (B) Western blot analysis using anti-flag antibodies to detect DDK-tagged wild type PRDM12 or the indicated human PRDM12 mutant proteins transiently transfected into HEK cells. Note that we failed to detect the truncation mutant S58fs. (C) Immunofluorescence analysis of HEK cells transiently transfected with DDK-tagged human wild type PRDM12 (WT) or the human R160C, D31Y, and E172D PRDM12 mutants. Arrows indicate protein aggregates of the mutant R160C and E172D protein as well as loss of nuclear staining for the mutant D31Y. The DDK-tag was visualized with anti-flag antibodies (green); nuclei are counterstained with DAPI (blue). Overlays appear in white. Representative images are shown. Magnifications 100×. (D) Real-time RT-PCR analysis of the expression of the indicated genes (±SEM) in stage 26 Xenopus animal cap explants isolated from embryos injected with noggin mRNA, together with wild type or mutated human Prdm12 mRNAs as indicated and treated with retinoic acid (RA). Data are presented as the mean ± SEM of 3 idependent experiments. Expression levels (fold change) were normalized to GAPDH and compared to the expression level of noggin-injected RA treated caps, which was defined as 1. Significance was determined by Student's t-test, where p-values were defined as: * P ≤ 0.05; **P ≤ 0.01; *** P ≤ 0.001.
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