Prdm12 Is Transcriptionally Active and Required for Nociceptor Function Throughout Life Publisher



Kokotovic T^{1, 2, 3} ; Langeslag M^{4, 5, 6} ; Lenartowicz EM^{1, 3} ; Manion J⁷ ; Fell CW^{1, 2, 3} ; Alehabib E⁸ ; Tafakhori A⁹ ; Darvish H¹⁰ ; Bellefroid EJ¹¹ ; Neely GG⁷ ; Kress M⁴ ; Penninger JM^{12, 13} ; Nagy V^{1, 2, 3}
Source: Frontiers in Molecular Neuroscience Published:2021

Abstract

PR domain-containing member 12 (PRDM12) is a key developmental transcription factor in sensory neuronal specification and survival. Patients with rare deleterious variants in PRDM12 are born with congenital insensitivity to pain (CIP) due to the complete absence of a subtype of peripheral neurons that detect pain. In this paper, we report two additional CIP cases with a novel homozygous PRDM12 variant. To elucidate the function of PRDM12 during mammalian development and adulthood, we generated temporal and spatial conditional mouse models. We find that PRDM12 is expressed throughout the adult nervous system. We observed that loss of PRDM12 during mid-sensory neurogenesis but not in the adult leads to reduced survival. Comparing cellular biophysical nociceptive properties in developmental and adult-onset PRDM12 deletion mouse models, we find that PRDM12 is necessary for proper nociceptive responses throughout life. However, we find that PRDM12 regulates distinct age-dependent transcriptional programs. Together, our results implicate PRDM12 as a viable therapeutic target for specific pain therapies even in adults. © Copyright © 2021 Kokotovic, Langeslag, Lenartowicz, Manion, Fell, Alehabib, Tafakhori, Darvish, Bellefroid, Neely, Kress, Penninger and Nagy.