Disease relevance of Ntf3

• 5. In mice lacking NT-3, the initial formation of the ganglion, as assessed at E10.5, is similar to that in wild-type animals [1].
• Mice deficient for neurotrophin-3 (NT-3) and its receptor, encoded by the trkC gene, show abnormal movements caused by the loss of sensory proprioceptive neurons [2].
• Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals [3].
• We conclude that endogenous NT-3 enhanced neuronal injury during acute stroke, possible by increasing oxygen-radical mediated cell death [3].
• To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia [3].

Psychiatry related information on Ntf3

• As in NT3 and TrkC null mice, the proprioception system of these mutants failed to assemble [4].
• Together, these findings demonstrate that NT-3 signaling counters Abeta-dependent neuronal cell death and may represent an innovative therapeutic intervention to limit neuronal death in Alzheimer disease [5].
• Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms [6].
• Wild-type (n=12) and mlc/NT-3 (n=12) male mice were tested in five procedures (in chronological order): lick dynamics, locomotor activity, grid ataxia, go-no-go discrimination procedure, and grip strength [7].

High impact information on Ntf3

• Interestingly, final target-derived NGF promotes expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT-3 [8].
• We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields [8].
• The observed defects are consistent with abnormalities in the survival and/or migration of cardiac neural crest early in embryogenesis and establish an essential role for neurotrophin 3 in regulating the development of the mammalian heart [9].
• Peripheral neuronal subpopulations expressing the TrkC receptor tyrosine kinase respond to Nt3 with enhanced survival, mitogenesis or cell migration and these neurons are lost in homozygous Nt3 null (-/-) mutant mice [9].
• Histological and echocardiographic image analysis of Nt3-/- animals reveal severe cardiovascular abnormalities including atrial and ventricular septal defects, and tetralogy of Fallot, resembling some of the most common congenital malformations in humans [9].

Chemical compound and disease context of Ntf3

• To test whether these isoforms have different functions related to axon outgrowth, full-length or tyrosine kinase-lacking TrkC receptors were overexpressed in embryonic dorsal root ganglion neurons maintained in explant cultures in neurotrophin-3 (NT-3)-containing media [10].
• Electrophysiological studies showed that the intramuscular injection of an adenovirus encoding NT-3 partially prevented the cisplatin-induced increase in sensory distal latencies [11].

Biological context of Ntf3

• Cotransfection of plasmids encoding gp145trkB and BDNF or NT-3 leads to transformation of recipient NIH 3T3 cells [12].
• NT-3 also enhanced neuronal cell death and the production of reactive oxygen species caused by oxidative damage inducing agents [3].
• In TrkC null and NT-3 null mice, Merkel cells differentiate initially, but undergo apoptosis perinatally [13].
• Site-specific interactions of neurotrophin-3 and fibroblast growth factor (FGF2) in the embryonic development of the mouse cochlear nucleus [14].
• Therefore, BDNF, NT-3, and NT-4 can also act as "epitheliotrophins" and may thus be intimately involved in the control of epidermal homeostasis [15].

Anatomical context of Ntf3

• Ntf3 transcript reductions are comparable to an adult model that uses a dominant negative form of ErbB4 expressed in the supporting cells and Schwann cells of the organ of Corti [16].
• Importantly, the number of muscle spindles in heterozygous mutant mice was half of that in control mice, indicating that NT-3 is present at limiting concentrations in the embryo [17].
• Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents [17].
• Furthermore, gp145trkB specifically binds BDNF and NT-3 in NIH 3T3 cells and in hippocampal cells, but does not bind NGF [18].
• Mice lacking neurotrophin-3 (NT-3) or its receptor, TrkC, lose many spiral ganglion cells predominantly in the basal turn of the cochlea [19].

Associations of Ntf3 with chemical compounds

• When neuroblasts migrated and differentiated, immunostaining was used for locating NT3 and TrkC in the morphogenetic sequence, bromodeoxyuridine for proliferation, and synaptic vesicle protein for synaptogenesis [14].
• Mice heterozygous for neurotrophin-3 display enhanced vulnerability to excitotoxicity in the striatum through increased expression of N-methyl-d-aspartate receptors [20].
• QUIN injection induced a decrease in dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32) protein levels that was higher in NT-3 +/- than in BDNF+/- or wild type animals [20].
• The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3 [21].
• Localization of nerve growth factor, neurotrophin-3, and glial cell line-derived neurotrophic factor in nestin-expressing reactive astrocytes in the caudate-putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57/Bl mice [22].

Physical interactions of Ntf3

• The p75 neurotrophin receptor has been implicated in neurotrophin binding and signaling for both NGF and NT3 [23].
• TrkC is a receptor tyrosine kinase that binds neurotrophin-3 (NT-3) with high affinity [24].
• Acidic fibroblast growth factor (aFGF) is a heparin-binding polypeptide that acts as a neurotrophic factor for certain central and peripheral neurons [25].

Regulatory relationships of Ntf3

• The p75 neurotrophin receptor influences NT-3 responsiveness of sympathetic neurons in vivo [26].
• In primary striatal cultures, NT-3 treatment induced an enhancement in NR2A, but not NR2B, protein levels [20].
• In conclusion, NT-3 regulates the expression of NMDAR subunits modifying striatal neuronal properties that confers the differential vulnerability to excitotoxicity in projection neurons and interneurons in the striatum [20].
• Our results show that NT3 expressed emporally and spatially in the place of BDNF is sufficient in some neuronal populations to compensate for the loss of BDNF [27].
• Here we provide evidence that both the mitogenic effect of bFGF and the differentiation-promoting effect of NT3 are linked with modifications of cell cycle kinetics in mouse cortical precursor cells [28].

Other interactions of Ntf3

• In these assays, BDNF elicits a response at least two orders of magnitude higher than NT-3 [12].
• Characterization of neurotrophin and Trk receptor functions in developing sensory ganglia: direct NT-3 activation of TrkB neurons in vivo [29].
• Many, but not all, of the NT3- and NT4-dependent neurons switch to BDNF at later stages [30].
• However, intrastriatal grafting of NT-3 secreting-cells in adult wild type mice produced a down-regulation of NR2A subunit [20].
• This expression of p75NTR by epithelial target cells required NT-3 but not adult innervation [31].

Analytical, diagnostic and therapeutic context of Ntf3

• Neurotrophin-3-deficient (NT-3-deficient) mice were generated by gene targeting [17].
• The results of our in situ hybridization experiments demonstrate that sensory neurons, sympathetic neurons, and motoneurons express brain-derived neurotrophic factor and/or neurotrophin-3 mRNAs during development in mouse [32].
• Dissection of NT3 functions in vivo by gene replacement strategy [4].
• Consistent with this, the addition of NT-3 to primary cortical cell cultures exacerbated neuronal death caused by oxygen-glucose deprivation [3].
• We determined by ELISA and reverse transcriptase-PCR that BDNF, NT-3, and NT-4 are expressed in C57BL/6 mouse skin [15].

References