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Cell Cycle. 2015;14(12):1799-808. doi: 10.1080/15384101.2015.1036209.

The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.

Author information

1
IMBA-Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria; UNSW Medicine, Sydney, Australia.

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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.

KEYWORDS:

BSA, bovine serum albumin; Brn3d, brain 3d; CGNL1, cyclin L1; ChIP, chromatin immunoprecipitation; DAPI, 4′,6-diamidino-2-phenylindole; DDK, DYKDDDDK epitope; Drgx, dorsal root ganglia homeobox; ECL, enhanced chemiluminescence; En1, engrailed-1; FDR, false discovery rate; FPKM, fragments per kilobase exon; GAPDH, glyceraldehyde 3-phospate dehydrogenase; GEO, gene expression omnibus; GFP, green fluorescent protein; HEK293, human embryonic kidney cell 293; HRP, horseraddish peroxidase; HSAN, hereditary and sensory autonomic neuropathy; Hamlet; Hmx3, H6 family homeobox 3; IL1R1, interleukin 1 receptor type 1; MO, morpholino oligonucleotide; NBT/BCIP, nitro blue tetrazolium / 5-bromo-4-chloro-3-indolyl-phosphate; PBS, phosphate buffered saline; PDB, protein data base; PMID, pubmed identification.; PRDM12; PRDM12, PR homology domain-containing member 12; RA, retinoic acid; RT-qPCR, real-time quantitative polymerase chain reaction; S1PR1, Sphi8ngosine-1-phosphate receptor 1; SET, Su(var)3–9 and ‘Enhancer of zeste’; Sncg, Synuclein Gamma (Breast Cancer-Specific Protein 1); TRH(DE), tryrotropin-releasing hormone degrading enzyme; TRHDE; TRHDE, tyrotropin-releasing hormone degrading enzyme; Tlx3, T-cell leukemia homeobox 3; nociception; pCMV6, plasmid cytomegalovirus; sensory neurons

PMID:
25891934
PMCID:
PMC4613559
DOI:
10.1080/15384101.2015.1036209
[Indexed for MEDLINE]
Free PMC Article

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