Sensory Neurogenesis and the Role of PRDM12 in Nociceptor Development and Function

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August 2021

Authors

Landy, Mark Andrew

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Abstract

Nociceptors are a set of peripheral neurons responsible for the detection of noxious stimuli. They function to alert us to the presence of potentially damaging internal and environmental threats, thereby playing an important role in allowing us to react and avoid danger. Unfortunately, for over 30% of the population, the sense of pain derived from nociception becomes maladaptive, leading to chronic painful conditions which carry an estimated economic burden of over USD 600 billion. While opioids are the current mainstay analgesic medication, they have a vast array of side effects, including risk of overdose and death, which makes their use in treatment of chronic conditions far from ideal. Recently, studies of genetic mutations leading to congenital insensitivity to pain (CIP) have provided a springboard for the development of novel analgesics targeting nociceptor function in the periphery. The identification of additional such mutations in the gene Prdm12 raised questions about processes inherent to nociceptor development and sensory neurogenesis as a whole, and what function this gene plays in mature primary afferent neurons. Over the course of my dissertation work I sought to address some of these questions by studying the development of nociceptive neurons in mice, and the effect of Prdm12-knockout on pain sensation. To establish a framework for sensory neuronal development, I first completed a birthdating study using a thymidine analog to permanently label cells undergoing their final mitotic divisions and identify them at later timepoints. With this, I show that there is no temporal difference in the birth rates of different nociceptor subtypes, but that most are born after touch and proprioceptive neurons. Next, using multiple models to knockout Prdm12 at various timepoints ranging from conception to adulthood, I then provide evidence that this is a key transcription factor for specification of the nociceptor population, but that its function likely changes over time. Loss of Prdm12 during development causes defects in nociception, but no behavioral phenotype was readily discernible following adult knockout. Instead, I show that Prdm12 appears to regulate a population of stem cell-like neurons, with an as-yet unknown role in dorsal root ganglia. Altogether my work highlights the role of Prdm12 in nociceptor development and lays the groundwork for additional studies to investigate the clinical relevance of this gene.

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