Prdm12 Directs Nociceptive Sensory Neuron Development by Regulating the Expression of the NGF Receptor TrkA

Desiderio, Simon; Vermeiren, Simon; Campenhout, Claude Van; Kricha, Sadia; Malki, Elisa; Richts, Sven; Fletcher, Emily V.; Vanwelden, Thomas; Schmidt, Béla Z.; Henningfeld, Kristine A.; Pieler, Tomas; Woods, C. Geoffrey; Nagy, Vanja; Verfaillie, Catherine M.; Bellefroid, Éric

doi:10.1016/j.celrep.2019.02.097

Cited by 55 publications

(113 citation statements)

References 76 publications

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“…It is highly conserved from mouse to human, with 98% protein identity, suggesting a highly conserved function, and opening the gateway for study in mouse models. Indeed, consistent with the idea of having a highly conserved function, loss-of-function of PRDM12 in humans or its homologs in Drosophila, frog embryos, and mice leads to abnormalities in sensory neuron development (Bartesaghi et al, 2019;Chen et al, 2015;Desiderio et al, 2019;Moore et al, 2004;Nagy et al, 2015). Additionally, Prdm12 is specifically expressed in myelinated Aδand unmyelinated C-fiber nociceptors into adulthood (Chen et al, 2015;Kinameri et al, 2008;Nagy et al, 2015;Sharma et al, 2020;Thelie et al, 2015;Usoskin et al, 2014).…”

Section: Introductionsupporting

confidence: 52%

“…Early reports indicated that PRDM12 promoted expression of sensory neuronal markers (Kinameri et al, 2008;Matsukawa et al, 2015;Thelie et al, 2015;Yang and Shinkai, 2013). Consistent with this, Prdm12 was found to be necessary for the initiation and maintenance of tropomyosin receptor kinase A (TRKA) expression, a marker for early nociceptor development (Desiderio et al, 2019). In addition, in the absence of Prdm12, the entire nociceptor lineage failed to develop.…”

Section: Introductionmentioning

confidence: 68%

“…However, the mechanism by which Prdm12 knockout leads to a deficiency in nociceptors is unclear. Work by Bartesaghi et al found evidence for decreased proliferation in Prdm12 knockout mice with no change in cell death (Bartesaghi et al, 2019), while work from Desiderio et al found the opposite, that there was no change in proliferation, but there was an increase in cell death (Desiderio et al, 2019). Differences in the way proliferation and cell death were quantitated in these studies could account for these discrepancies.…”

Section: Introductionmentioning

confidence: 90%

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Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

Landy

Goyal

Casey

et al. 2020

Preprint

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Prdm12 is as a key transcription factor in nociceptor neurogenesis. Mutations of Prdm12 cause Congenital Insensitivity to Pain (CIP) due to failure of nociceptor development. However, precisely how deletion of Prdm12 during development or adulthood affects nociception is unknown. Here, we employ tissue- and temporal-specific knockout mouse models to test the function of Prdm12 during development and in adulthood. We find that constitutive loss of Prdm12 causes deficiencies in proliferation during sensory neurogenesis. We also demonstrate that conditional knockout from dorsal root ganglia (DRGs) during embryogenesis causes defects in nociception. In contrast, we find that in adult DRGs, Prdm12 is dispensable for pain sensation and injury-induced hypersensitivity. Using transcriptomic analysis, we found unique changes in adult Prdm12 knockout DRGs compared to embryonic knockout, and that PRDM12 is likely a transcriptional activator in the adult. Overall, we find that the function of PRDM12 changes over developmental time.

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Section: Introductionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 90%

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Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

Landy

Goyal

Casey

et al. 2020

Preprint

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“…To differentiate hESCs to sensory neurons, we used a previously described protocol (Chambers et al, ; Desiderio et al, ; Young et al, ). Briefly, neuronal differentiation protocol is executed in different phases, starting with the formation of neurectoderm (Chambers et al, ).…”

Section: Methodsmentioning

confidence: 99%

Functional expression and pharmacological modulation of TRPM3 in human sensory neurons

Vangeel

Benoit

Miron

et al. 2020

British J Pharmacology

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Background and Purpose:The transient receptor potential (TRP) ion channel TRPM3 functions as a noxious heat sensor, plays a key role in acute pain sensation and inflammatory hyperalgesia in rodents. Despite its potential as a novel analgesic drug target, little is known about the expression, function and modulation in the humans. Experimental Approach:We studied TRPM3 in freshly isolated human dorsal root ganglion (hDRG) neurons and human stem cell-derived sensory (hSCDS) neurons.Expression was analysed at the mRNA level using RT-qPCR. Channel function was assessed using Fura-2-based calcium imaging and whole-cell patch-clamp recordings. Key Results: TRPM3 was detected at the mRNA level in both hDRG and hSCDS neurons. The TRPM3 agonists pregnenolone sulphate (PS) and CIM0216 evoked robust intracellular Ca 2+ responses in 52% of hDRG and 58% of hSCDS neurons. Whole-cell patch-clamp recordings in hSCDS neurons revealed pregnenolone sulphate (PS)-and CIM0216-evoked currents exhibiting the characteristic current-voltage relation of TRPM3. PS-induced calcium responses in hSCDS neurons were reversed in a dosedependent manner by the flavonoid isosakuranetin and by antiseizure drug primidone. Finally, the μ-opioid receptor agonist DAMGO and the GABA B receptor agonist baclofen inhibited PS-evoked TRPM3 responses in a subset of hSCDS neurons. Conclusion and Implications: These results provide the first direct evidence of functional expression of the pain receptor TRPM3 in human sensory neurons, largely mirroring the channel's properties observed in mouse sensory neurons. hSCDS neurons represent a valuable and readily accessible in vitro model to study TRPM3 regulation and pharmacology in a relevant human cellular context.

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“…2a, h, i). Both factors play an important role in lineage specification in the developing spinal cord [32][33][34] . However, whether these factors play a similar role in the hypothalamus has not been studied.…”

mentioning

confidence: 99%

Transcriptomic Profiling of Developing Melanocortin Neurons Reveals a Role for Prdm12 in Energy Balance

Chen

Wyler

et al. 2019

Preprint

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The hypothalamus is a critical regulator of many physiological processes essential for life. In the adult brain, each anatomically-defined hypothalamic nucleus consists of functionally heterogeneous neuronal subpopulations that dictate distinct survival behaviors. Nevertheless, how rich neuronal identities are established in the developing hypothalamus remains poorly understood.Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive.We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons with whole-genome RNA sequencing (RNA-seq). Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons.Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but was absent in NPY/AgRP neurons. Selective ablation of Prdm12 in postmitotic POMC neurons led to early-onset obesity, accelerated linear growth, as well as impaired glucose tolerance, which recapitulates symptoms of POMC/MC4R deficiency in humans. These findings, therefore, establish a previously-unrecognized role for Prdm12 in energy balance. Furthermore, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the developing hypothalamus as well as the developmental origins of diverse survival behaviors.

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Prdm12 Directs Nociceptive Sensory Neuron Development by Regulating the Expression of the NGF Receptor TrkA

Cited by 55 publications

References 76 publications

Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

Functional expression and pharmacological modulation of TRPM3 in human sensory neurons

Transcriptomic Profiling of Developing Melanocortin Neurons Reveals a Role for Prdm12 in Energy Balance

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