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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
.
???displayArticle.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.
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 100Ã. (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.
,
Corrigendum.
2015,
Pubmed
Ainsley,
Enhanced locomotion caused by loss of the Drosophila DEG/ENaC protein Pickpocket1.
2003,
Pubmed
Aldrich,
The amnesiac gene is involved in the regulation of thermal nociception in Drosophila melanogaster.
2010,
Pubmed
Andrews,
Sequoia regulates cell fate decisions in the external sensory organs of adult Drosophila.
2009,
Pubmed
Auer-Grumbach,
Molecular genetics of hereditary sensory neuropathies.
2006,
Pubmed
Basbaum,
Cellular and molecular mechanisms of pain.
2009,
Pubmed
Boschi,
Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine.
1983,
Pubmed
Brade,
The amphibian second heart field: Xenopus islet-1 is required for cardiovascular development.
2007,
Pubmed
,
Xenbase
Chattopadhyay,
Local and global methods of assessing thermal nociception in Drosophila larvae.
2012,
Pubmed
Chen,
The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord.
2001,
Pubmed
Cupp,
Age-related changes in prefrontal cortex of Macaca mulatta: quantitative analysis of dendritic branching patterns.
1980,
Pubmed
Dietzl,
A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila.
2007,
Pubmed
Ernsberger,
Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia.
2009,
Pubmed
Eroglu,
SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells.
2014,
Pubmed
Eto,
Taltirelin, a thyrotropin-releasing hormone analog, alleviates mechanical allodynia through activation of descending monoaminergic neurons in persistent inflammatory pain.
2011,
Pubmed
Feng,
Pivotal role of hmx2 and hmx3 in zebrafish inner ear and lateral line development.
2010,
Pubmed
Gelernter,
Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations.
2006,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Kang,
Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception.
2010,
Pubmed
Khuong,
Conserved systems and functional genomic assessment of nociception.
2013,
Pubmed
Kim,
A transcription factor for cold sensation!
2005,
Pubmed
Lee,
Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways.
2004,
Pubmed
Lopes,
Tlx3 and Runx1 act in combination to coordinate the development of a cohort of nociceptors, thermoceptors, and pruriceptors.
2012,
Pubmed
Lumpkin,
Mechanisms of sensory transduction in the skin.
2007,
Pubmed
Mair,
Genetic evidence for involvement of neuronally expressed S1P₁ receptor in nociceptor sensitization and inflammatory pain.
2011,
Pubmed
Manev,
Drosophila model for in vivo pharmacological analgesia research.
2004,
Pubmed
Matsukawa,
The requirement of histone modification by PRDM12 and Kdm4a for the development of pre-placodal ectoderm and neural crest in Xenopus.
2015,
Pubmed
,
Xenbase
McEvilly,
Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons.
1996,
Pubmed
Moore,
hamlet, a binary genetic switch between single- and multiple- dendrite neuron morphology.
2002,
Pubmed
Moore,
Conversion of neurons and glia to external-cell fates in the external sensory organs of Drosophila hamlet mutants by a cousin-cousin cell-type respecification.
2004,
Pubmed
Neely,
TrpA1 regulates thermal nociception in Drosophila.
2011,
Pubmed
Neely,
A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene.
2010,
Pubmed
Patterson,
Hox11-family genes XHox11 and XHox11L2 in xenopus: XHox11L2 expression is restricted to a subset of the primary sensory neurons.
1999,
Pubmed
,
Xenbase
Reid,
A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion.
2004,
Pubmed
Schneider,
NIH Image to ImageJ: 25 years of image analysis.
2012,
Pubmed
Simonetti,
Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain.
2013,
Pubmed
Sun,
A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs.
2008,
Pubmed
Tanabe,
The synthetic TRH analogue taltirelin exerts modality-specific antinociceptive effects via distinct descending monoaminergic systems.
2007,
Pubmed
Thélie,
Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus.
2015,
Pubmed
,
Xenbase
Tracey,
The cerebral signature for pain perception and its modulation.
2007,
Pubmed
Tracey,
painless, a Drosophila gene essential for nociception.
2003,
Pubmed
Wang,
Characterization of three synuclein genes in Xenopus laevis.
2011,
Pubmed
,
Xenbase
Wu,
Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease.
2005,
Pubmed
Xie,
Knockdown of the sphingosine-1-phosphate receptor S1PR1 reduces pain behaviors induced by local inflammation of the rat sensory ganglion.
2012,
Pubmed
Xu,
Thermal nociception in adult Drosophila: behavioral characterization and the role of the painless gene.
2006,
Pubmed
Yang,
Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples.
2007,
Pubmed
Zannino,
prdm12b specifies the p1 progenitor domain and reveals a role for V1 interneurons in swim movements.
2014,
Pubmed
Zhong,
Pickpocket is a DEG/ENaC protein required for mechanical nociception in Drosophila larvae.
2010,
Pubmed
