Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior

The long-range goal is to identify the genetic programs controlling the formationsof specific sensory pathways and to gain insight into the molecular and cellular basis of pain perception.In this renewal application, we try to address two major knowledge gaps. First, most clinically relevantpain is derived from deep tissues, such as muscle, joint, bone, and visceral organs. Despite this clinicalsignificance, the molecular and cellular basis of “deep” pain is still poorly understood, which is in starkcontrast to the tremendous progress made in the past decades in understanding cutaneous pain. InAim 1 studies, we will establish a molecular map for sensory neurons innervating distinct deep tissues.We will also determine if Meis1 represents the first transcription factor that controls the development ofdeep tissue sensory neurons. Second, the cellular basis of mechanical allodynia (pain evoked byinnocuous mechanical stimuli), a hallmark for most, if not all, chronic pain disorders, needs furtherclarification. In case of neuropathic pain, it was proposed that central disinhibition will allow lowthreshold myelinated A mechanoreceptors to directly activate the pain pathways. However, a recentstudy proposed that unmyelinated low threshold c-mechanoreceptors, marked by the expression of thevesticular glutamate transporter VGLUT3, may play an essential role in the readout of the mechanicalallodynia. Our preliminary genetic fate-mapping studies show that VGLUT3 lineage neurons are in factcomposed of both 1) unmyelinated c-mechanoreceptors that form free nerve endings in the skinepidermis and lanceolate endings around hair follicles, and 2) myelinated m-mechanoreceptors thatform the Merkel-cell neurite complex. In Aim 2, we will determine if Zfp521, a transcription factorexpressed exclusively in VGLUT3 lineage c-mechanoreceptor, is necessary for the development ofthese c-mechnaoreceptors. We will also determine if mechanical allodynia is differentially affected inmice that will have a selective developmental defect in VGLUT3 lineage c-mechanoreceptors or adefect in the VGLUT3-expressing Merkel cell-neurite complex.