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Transcriptional regulator PRDM12 is essential for human pain perception.

ABSTRACT: Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

SUBMITTER: Chen YC

PROVIDER: S-EPMC7212047 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Transcriptional regulator PRDM12 is essential for human pain perception.

Chen Ya-Chun YC Auer-Grumbach Michaela M Matsukawa Shinya S Zitzelsberger Manuela M Themistocleous Andreas C AC Strom Tim M TM Samara Chrysanthi C Moore Adrian W AW Cho Lily Ting-Yin LT Young Gareth T GT Weiss Caecilia C Schabhüttl Maria M Stucka Rolf R Schmid Annina B AB Parman Yesim Y Graul-Neumann Luitgard L Heinritz Wolfram W Passarge Eberhard E Watson Rosemarie M RM Hertz Jens Michael JM Moog Ute U Baumgartner Manuela M Valente Enza Maria EM Pereira Diego D Restrepo Carlos M CM Katona Istvan I Dusl Marina M Stendel Claudia C Wieland Thomas T Stafford Fay F Reimann Frank F von Au Katja K Finke Christian C Willems Patrick J PJ Nahorski Michael S MS Shaikh Samiha S SS Carvalho Ofélia P OP Nicholas Adeline K AK Karbani Gulshan G McAleer Maeve A MA Cilio Maria Roberta MR McHugh John C JC Murphy Sinead M SM Irvine Alan D AD Jensen Uffe Birk UB Windhager Reinhard R Weis Joachim J Bergmann Carsten C Rautenstrauss Bernd B Baets Jonathan J De Jonghe Peter P Reilly Mary M MM Kropatsch Regina R Kurth Ingo I Chrast Roman R Michiue Tatsuo T Bennett David L H DL Woods C Geoffrey CG Senderek Jan J

Nature genetics 20150525 7

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology ...[more]

PMID: 26005867

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Project description:Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat-Wilson syndrome.SIGNIFICANCE STATEMENT Bergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat-Wilson syndrome.

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Transcriptional regulator PRDM12 is essential for human pain perception.

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Transcriptional regulator PRDM12 is essential for human pain perception.

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