Local circuit association neurons in the superficial dorsal horn subserve important functions in the gating and transduction of somatosensory information from the periphery. As such, these neurons are important components of pain pathways in the spinal cord. We have recently shown dorsal association interneurons are derived from an embryonic population of cells that express Lbxl (Gross et al., 2002). However, very little is known about how these spinal neurons differentiate to form the many specialized functional cell types that are found in the adult spinal cord. In this grant, we will examine how Lbx 1 neurons are specified, focusing on the role of the Gshl, Gsh2 and Gbx2 homeobox genes in Lbxl neuron progenitors. We will also determine how late-born Lbx I neurons differentiate as either inhibitory or excitatory neurons, and ask whether Notch signaling regulates the developmental switch that selects between excitatory and inhibitory cell fates. The observation that Pax2 is required for dorsal GABAergic and glycinergic development makes these dorsal horn interneurons an excellent model system for probing the molecular mechanisms that regulate the acquisition of an inhibitory neurotransmitter phenotype. We will examine the role that the Pax2, Lhxl/5 and the Ets2 transcription factors play in the development of dorsal inhibitory cell types. In particular, we will ask whether these factors, or other factors that are downstream of Pax2, regulate the expression of genes that are required for the inhibitory transmission machinery. Finally, we will generate conditional Pax2 knockout mice and use these mice to test whether Pax2 has a 'late' function in dorsal inhibitory neurons. We will also use the Pax2 conditional KO mice to begin assessing the function of GABAergic neurons in the dorsal horn with respect to the transduction of noxious and non-noxious stimuli, as well as the development of pain neuropathies such as hyperalgesia. These studies will provide important insights into the development and organization of neural circuits in the dorsal horn that sense and relay pain. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031978-14
Application #
7222658
Study Section
Development - 1 Study Section (DEV)
Program Officer
Riddle, Robert D
Project Start
1993-08-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
14
Fiscal Year
2007
Total Cost
$495,140
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Del Barrio, Marta Garcia; Bourane, Steeve; Grossmann, Katja et al. (2013) A transcription factor code defines nine sensory interneuron subtypes in the mechanosensory area of the spinal cord. PLoS One 8:e77928
Grossmann, Katja S; Giraudin, Aurore; Britz, Olivier et al. (2010) Genetic dissection of rhythmic motor networks in mice. Prog Brain Res 187:19-37
Garcia-Campmany, Lidia; Stam, Floor J; Goulding, Martyn (2010) From circuits to behaviour: motor networks in vertebrates. Curr Opin Neurobiol 20:116-25
Goulding, Martyn (2009) Circuits controlling vertebrate locomotion: moving in a new direction. Nat Rev Neurosci 10:507-18
Pillai, Andrea; Mansouri, Ahmed; Behringer, Richard et al. (2007) Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord. Development 134:357-66
Gross, M K; Moran-Rivard, L; Velasquez, T et al. (2000) Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127:413-24
Daston, G; Lamar, E; Olivier, M et al. (1996) Pax-3 is necessary for migration but not differentiation of limb muscle precursors in the mouse. Development 122:1017-27
Goulding, M; Lumsden, A; Paquette, A J (1994) Regulation of Pax-3 expression in the dermomyotome and its role in muscle development. Development 120:957-71