title: The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception.
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.
authors.affiliation: IMBA-Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria; UNSW Medicine, Sydney, Australia.
authors.forename: Vanja
authors.initials: V
authors.lastname: Nagy
authors.forename: Tiffany
authors.initials: T
authors.lastname: Cole
authors.forename: Claude
authors.initials: C
authors.lastname: Van Campenhout
authors.forename: Thang M
authors.initials: TM
authors.lastname: Khoung
authors.forename: Calvin
authors.initials: C
authors.lastname: Leung
authors.forename: Simon
authors.initials: S
authors.lastname: Vermeiren
authors.forename: Maria
authors.initials: M
authors.lastname: Novatchkova
authors.forename: Daniel
authors.initials: D
authors.lastname: Wenzel
authors.forename: Domagoj
authors.initials: D
authors.lastname: Cikes
authors.forename: Anton A
authors.initials: AA
authors.lastname: Polyansky
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.forename: Arabella
authors.initials: A
authors.lastname: Meixner
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bellefroid
authors.forename: G Gregory
authors.initials: GG
authors.lastname: Neely
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D019070:Cell Lineage; D018360:Crystallography, X-Ray; D004330:Drosophila; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D058748:Pain Perception; D017434:Protein Structure, Tertiary; D011984:Sensory Receptor Cells / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C587499:Prdm12 protein, human
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