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

Abstract

These authors contributed equally to this work.Keywords: Hamlet, nociception, PRDM12, sensory neurons, TRHDE Abbreviation: PRDM12, PR homology domain-containing member 12; HSAN, hereditary and sensory autonomic neuropathy; TRHDE, tyrotropin-releasing hormone degrading enzyme; RA, retinoic acid; Brn3d, brain 3d; Tlx3, T-cell leukemia homeobox 3; Hmx3, H6 family homeobox 3; Drgx, dorsal root ganglia homeobox; Sncg, Synuclein Gamma (Breast Cancer-Specific Protein 1); En1, engrailed-1; RT-qPCR, real-time quantitative polymerase chain reaction; MO, morpholino oligonucleotide; ChIP, chromatin immunoprecipitation; S1PR1, Sphi8ngosine-1-phosphate receptor 1; CGNL1, cyclin L1; IL1R1, interleukin 1 receptor type 1; TRH(DE), tryrotropin-releasing hormone degrading enzyme; pCMV6, plasmid cytomegalovirus; DDK, DYKDDDDK epitope; GAPDH, glyceraldehyde 3-phospate dehydrogenase; NBT/BCIP, nitro blue tetrazolium / 5-bromo-4-chloro-3-indolyl-phosphate; SET, Su(var)3-9 and 'Enhancer of zeste'; PDB, protein data base; HEK293, human embryonic kidney cell 293; PBS, phosphate buffered saline; DAPI, 4 0 ,6-diamidino-2-phenylindole; GFP, green fluorescent protein; BSA, bovine serum albumin; HRP, horseraddish peroxidase; ECL, enhanced chemiluminescence; FPKM, fragments per kilobase exon; FDR, false discovery rate; GEO, gene expression omnibus; PMID, pubmed identification.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.

Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

“…The encoded protein is an extracellular peptidase that specifically cleaves and inactivates the neuropeptide thyrotropin-releasing hormone (Bauer et al, 1999). Concurring with this, knockdown of TRHDE in Drosophila sensory neurons is known to result in altered cellular morphology, impaired nociception and the sensory response to (potentially) harmful stimuli (Nagy et al, 2015). In our study, carriers of the minor allele showed a slower increase of cerebellum white matter, followed by reduced decline in older age (Supplementary Figure S5).…”

Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus

“…By contrast, our data indicate that Xenopus or mouse Prdm12 promotes En1 + V1 INs when overexpressed in the frog or chick embryo. Human PRDM12 also induces en1 when overexpressed in the frog (Nagy et al, 2015). The reasons for this functional difference between zebrafish and tetrapode vertebrate Prdm12 are unclear and remain to be determined.…”

“…Prdm12 is highly conserved during evolution (Nagy et al, 2015), and we identified orthologous sequences in the chicken and the cephalochordate amphioxus (Branchiostoma lanceolatum), a basal chordate (supplementary material Fig. S1).…”

“…In a recent study, different homozygous mutations have been identified throughout Prdm12 that all abrogates its histone-modifying activity (Chen et al, 2015). Some of these mutated forms of Prdm12, when overexpressed in Xenopus, exhibit an impaired activity to induce en1 (Nagy et al, 2015). It remains to be tested whether the amphioxus Prdm12 is inactive because of its impaired histonemodifying potential.…”

Analysis of the association of the PRDM12 gene with pain sensitivity in individuals with psychoactive substance dependence

“…Ген PRDM12 кодирует эпигенетический регулятор, который является ключевым в процессе мейоза, участвует в нейрогенезе и влияет на свойства нервных клеток [18,24]. PRDM12 необходим для разви-тия сенсорного нейрона и восприятия боли [17,[25][26][27]. Было показано участие гена PRDM12 в модуляции ноцицепторов и сенсорных нейронов у эмбрионов Xenopus [17].…”