The long-range goal of this project is to investigate genetic programs that control pain relay sensory neuron phenotypes in the dorsal spinal cord. Recently, my colleagues and I have compiled a genome-scale expression map of transcription factors in the mouse nervous system. Subsequent genetic studies demonstrate that Tlx3, a homeobox class transcription factor, is a pivotal regulator of spinal relay sensory neurons, including specification of glutamate neurotransmitters. Furthermore, persistent Tlx3 expression in adult animals is confined to superficial laminae, where putative pain relay neurons are located. The research described here builds upon this preliminary work. The goal of our research over the next five years is to illustrate the roles of Tlx3 in regulating spinal relay nociceptor phenotypes and pain behaviors and to gain insights into the molecular and cellular basis underlying pain perception.
In the past year (2008-2009), we have made the following major progresses. First, we find that besides controlling glutamatergic versus GABAergic neuronal cell fates, Tlx3 and another homeobox gene Lbx1 also control two sets of peptidergic transmitter phenotypes in the dorsal spinal cord. Second, we found that Tlx3 operates at top hierarchy and activates of a range of downstream transcription factors, each of which controls a portion of Tlx3-dependent relay neuron phenotype. Third, we have made Tlx3 conditional knockouts and demonstrated that Tlx3 is required for heat and mechanical pain sensation.
