The long-term goal of this proposal is to investigate the molecular and cellular mechanisms that underlie the establishment of nociceptive circuits in the dorsal spinal cord. The function of circuits that sense noxious stimuli critically depends on precise neuronal connectivity between primary sensory afferents and spinal cord dorsal horn neurons. However, the molecular and cellular mechanisms that govern the developing dorsal horn circuits are poorly understood. Drg11, a paired homeodomain transcription factor, is expressed by both primary sensory neurons in dorsal root ganglia (DRG) and their central targets in the dorsal horn. In Drg11-/-mice, the spatio-temporal patterning of primary sensory afferent fiber ingrowth into the dorsal horn is disrupted. A cascade of sequelae consequent to these initial defects lead to cell death in the dorsal horn, and significantly attenuated responses to noxious stimuli in adults. Lmx1b, a lim homeodomain transcription factor and an upstream regulator of Drg11, is expressed in the dorsal horn but not in the DRG. In Lmx1b-/-mice, the entry of primary afferents in the dorsal horn is virtually blocked from the beginning. Therefore, Drg11 and Lmx1b are essential transcriptional determinants of the mechanisms that underlie the formation of pain circuits in mammals. Here we propose to study the precise role of Drg11 and Lmx1b in dorsal horn circuits by further analyzing the phenotype of Drg11-/- and Lmx1b-/- mice using both in vivo and in vitro approaches. We will also determine the roles of Drg11 and Lmx1b during postnatal dorsal horn development by generating Drg11 and Lmx1b conditional knockouts. Finally, we have initiated the search for dorsal horn-specific genes and will dissect the genetic cascade that controls the development of the dorsal spinal cord. The proposed study should provide a clearer molecular and cellular understanding of Drg11 and Lmx1b in the formation of dorsal horn nociceptive circuits. As defects in dorsal horn development could have a severe consequence on pain sensation, our work will ultimately lead to a better understanding of pain circuits and thus treatment of pain, a major clinical problem in human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043968-02
Application #
6625789
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Chiu, Arlene Y
Project Start
2002-04-15
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$290,700
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zhao, Zhong-Qiu; Gao, Yong-Jing; Sun, Yan-Gang et al. (2007) Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward. Proc Natl Acad Sci U S A 104:14519-24
Li, Mei-Zhang; Wang, Jin-Shan; Jiang, Dao-Jun et al. (2006) Molecular mapping of developing dorsal horn-enriched genes by microarray and dorsal/ventral subtractive screening. Dev Biol 292:555-64
Ding, Yu-Qiang; Xiang, Chuan-Xi; Chen, Zhou-Feng (2005) Generation and characterization of the PKC gamma-Cre mouse line. Genesis 43:28-33
Ding, Yu-Qiang; Kim, Ji-Young; Xu, Yong-Sheng et al. (2005) Ventral migration of early-born neurons requires Dcc and is essential for the projections of primary afferents in the spinal cord. Development 132:2047-56
Dunston, Jennifer A; Reimschisel, Tyler; Ding, Yu-Qiang et al. (2005) A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression. Eur J Hum Genet 13:330-5
Ding, Yu-Qiang; Yin, Jun; Kania, Artur et al. (2004) Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord. Development 131:3693-703