In experiments with mice, researchers have found that eliminating what appears to be a master genetic switch for the development of pain-sensing neurons knocks out the animals' response to "neuropathic pain." Such pain is abnormal pain that outlasts the injury and is associated with nerve and/or central nervous system changes. The animals rendered deficient in the gene, called Runx1, also showed lack of response to discomfort caused by heat and cold and inflammation. The researchers said that their findings, reported in the February 2, 2006, issue of Neuron, could have implications for the design of improved pain therapies.
In their experiments, Qiufu Ma and colleagues studied the Runx1 gene because past research had shown it to code for a protein "transcription factor," which is a master regulator of multiple genes. Runx1 is one of a group of proteins that are key players involved in transmitting external sensory information, like pain and the perception of movement, to the spinal cord. In two other related papers in the same issue, Silvia Arber and colleagues and Tom Jessell and colleagues examine related aspects of the biological importance underlying the Runx transcription factors.
Runx1 was known to be expressed only in sensory nerve cells called "nociceptive" cells, involved in sensing pain. Such pain-sensing cells function by translating painful stimuli into nerve signals via specialized pores called "ion channels" in the neurons, as well as specialized receptors. The researchers' studies of Runx1 in these cells revealed that during embryonic development, the gene is characteristically expressed in pain-receptor cells involved in neuropathic pain. When they knocked out the gene, they found that the normal development of such specialized nerve cells was impaired. The animals had lost ion channels known to be involved in reacting to painful heat or cold, as well as those involved in pain due to damaged tissue. The researchers also found that the Runx1-deficient animals showed deficient wiring of certain types of pain neurons.
In key experiments, the researchers measured the Runx1-deficient animals' response to four types of pain--thermal, mechanical, inflammatory, and neuropathic.
The researchers produced a pain response by subjecting the animals' hindpaw to either the cold of acetone or an uncomfortably warm plate (thermal); the uncomfortable prick of a filament (mechanical); an injection of an inflammation-inducing chemical (inflammatory); or nerve damage (neuropathic). They quantified the animals' response by measuring how long the animals lifted or licked their affected paw in response to the treatments.
Ma and his colleagues found that, while the deficient animals showed normal response to mechanical pain, they showed significantly lowered thermal, neuropathic, and inflammatory pain response.
The researchers concluded that while the diverse specialized components of the pain-sensing machinery could be established in a piecemeal fashion, "Our data, however, provide strong evidence that Runx1 is required to specify the receptive properties of a large cohort of nociceptive sensory neurons." They also concluded that the dual functions they discovered for Runx1--controlling specification of sensory neurons and regulating how they target their wiring--"form a genetic basis for the assembly of specific neural circuits for nociceptive information processing.
"Finally, the identification of a core transcriptional control program for many of the ion channels and receptors known to transduce noxious stimuli has intriguing implications for the design of more effective pain therapies," they wrote.
Chih-Li Chen, Yang Liu, Chuan Cen, Omar Abdel Samad, and Qiufu Ma of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA; Daniel C. Broom and Clifford J. Woolf of Massachusetts General Hospital and Harvard Medical School in Charlestown, MA; Albert I. Chen, Joriene C. de Nooij and Thomas M. Jessell of Howard Hughes Medical Institute and Columbia University in New York, NY; Zhe Li of Dartmouth Medical School in Hanover, NH. Ina Kramer, Markus Sigrist, and Silvia Arber of the University of Basel and Friedrich Miescher Institute in Basel, Switzerland; Ichiro Taniuchi of Howard Hughes Medical Institute and New York University School of Medicine in New York, NY.
This work was supported by grants from the National Institutes of Health to Q.M. and C.J.W. C.C. is a fellow of Charles King Medical foundation, J.C.D. is a fellow of Helen Hay Whitney Foundation, and Q.M. is a Claudia Adams Barr Scholar and a Pew Scholar in Biomedical Sciences. I.K., M.S., and S.A. were supported by a grant from the Swiss National Science Foundation, by the Kanton of Basel-Stadt, and by the Novartis Research Foundation. T.M.J. is supported by grants from the Human Frontier Science Program, National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and The Leila and Harold Mathers Foundation and is a Howard Hughes Medical Institute Investigator. J.C.d.N. was a post-doctoral fellow of the Helen Hay Whitney Foundation.
Chen et al.: "Runx1 Determines Nociceptive Sensory Neuron Phenotype and Is Required for Thermal and Neuropathic Pain." Publishing in Neuron 49, 1-13, February 2, 2006. DOI 10.1016/j.neuron.2005.10.036.
Kramer et al.: "A Role for Runx Transcription Factor Signaling in Dorsal Root Ganglion Sensory Neuron Diversification." Publishing in Neuron 49, 1-15, February 2, 2006. DOI 10.1016/j.neuron.2006.01.008
Chen et al.: "Graded Activity of Transcription Factor Runx3 Specifies the Laminar Termination Pattern of Sensory Axons in the Developing Spinal Cord." Publishing in Neuron 49, 1-14, February 2, 2006. DOI 10.1016/j.neuron.2005.12.028
(C) 2006 - Cell Press
Message posted by: Frank S. Zollmann
Variants Associated with Pediatric Allergic Disorder
Mutations in PHF6 Found in T-Cell Leukemia
Genetic Risk Variant for Urinary Bladder Cancer
Antibody Has Therapeutic Effect on Mice with ALS
Regulating P53 Activity in Cancer Cells
Anti-RNA Therapy Counters Breast Cancer Spread
Mitochondrial DNA Diversity
The Power of RNA Sequencing
‘Pro-Ageing' Therapy for Cancer?
Niche Genetics Influence Leukaemia
Molecular Biology: Clinical Promise for RNA Interference
Chemoprevention Cocktail for Colon Cancer
more news ...