Ongoing drug use in an opiate-addicted individual could be reinforced by withdrawal reactions that occur when drug use is halted abruptly. 1 Overactivity and disinhibition of brainstem noradrenergic neurons is thought to be a key mechanism for the hyperautonomic state and for many of the somatic symptoms that occur during acute withdrawal 2 and also for the acquisition of avoidance behaviors after occurrence of withdrawal reactions. 3 Little is known about endogenous factors that regulate noradrenergic neuron function and opiate withdrawal-related behaviors. Molecules of the nerve growth factor family may influence neuronal health and plasticity both in the developing and in the adult brain, including the reward and addiction circuitry. 4 Brainstem noradrenergic neurons of the adult rodent and primate brain express the neurotrophin-3 (NT-3) high affinity receptor, TrkC, 5-7 as well as the brain derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) receptor TrkB. In selected neuronal populations, NT-3 may promote growth and survival by binding to TrkB or TrkA, the high affinitity receptor for nerve growth factor (NGF). [8][9][10] Although levels of NT-3 and TrkC mRNA are altered in several brain areas during opiate withdrawal, 5 in vivo evidence of a role for NT-3 in opiate withdrawal and noradrenergic neuron function is still lacking. The perinatal lethality of conventional NT-3 knock-out mice, 11,12 due to major cardiovascular malformations, 13 prevented the use of these mice to study NT-3 in the adult brain. Using a conditional knock-out strategy with Cre/loxP mediated NT-3 gene deletion that results in complete loss of NT-3 in the central nervous system in mice with normal viability, fertility and lifespan, 14 we show here for the first time that NT-3 modulates electrophysiological responses and neurochemistry of brainstem noradrenergic neurons and that NT-3 is essential both for opiate withdrawal-induced avoidance behavior and for the somatic symptoms that occur during acute withdrawal. NT-3 modulates expression of tyrosine hydroxylase but is not essential for survival of noradrenergic neuronsWe used two transgenic lines, a conditional NT3 mutant 14 and a transgenic line carrying an NT3 transgene under the control of the DBH promoter to examine the consequences of NT3 deficiency as well as NT3 overexpression in opiate withdrawal reactions and in noradrenergic neuron function in vivo. Expression of the recombinase cre under control of the nestin promoter results in complete deletion of NT-3 during prenatal development of the brain and spinal cord. 14 To ascertain ubiquitous nestin-cre expression, a reporter line that expressed beta-galactosidase in all tissues upon cre-mediated removal of a stop translation sequence 15 was crossed with the nestin-cre transgenic line. The results shown in Figure 1a-c indicate that cre-mediated recombination is complete throughout the brain, consistent with previous Northern blot results. 14 In adult brain, NT-3 has been implicated in survival of noradrenergic neuron...

ABSTRACT. The objective of this study was the development of a gene/ protein interaction network for primary myelofibrosis based on gene expression, and the enrichment analysis of KEGG pathways underlying the molecular complexes in this network. To achieve this, genes involved in primary myelofibrosis were selected from the OMIM database. A gene/ protein interaction network for primary myelofibrosis was obtained through Cytoscape with the literature mining performed using the Agilent Literature Search plugin. The molecular complexes in the network were detected by ClusterViz plugin and KEGG pathway enrichment of molecular complexes was performed using DAVID online. We found 75 genes associated with primary myelofibrosis in the OMIM database. The gene/protein interaction network of primary myelofibrosis contained 608 nodes, 2086 edges, and 16127 Gene/protein interaction networks and enrichment analysis ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 16126-16132 (2015) 4 molecular complexes with a correlation integral value greater than 4. Molecular complexes involved in KEGG pathways are related to cytokine regulation, immune function regulation, ECM-receptor interaction, focal adhesion, actin cytoskeleton regulation, cell adhesion molecules, and other biological behavior of tumors, which can provide a reliable direction for the treatment of primary myelofibrosis and the bioinformatic foundation for further understanding the molecular mechanisms of this disease.