Naturally Occurring Truncated trkB Receptors Have Dominant Inhibitory Effects on Brain-Derived Neurotrophic Factor Signaling

Eide, Fernette F.; Vining, Ella R.; Eide, Brock; Zang, Keling; Wang, Xiaoyun; Reichardt, Louis F.

doi:10.1523/jneurosci.16-10-03123.1996

Cited by 437 publications

(317 citation statements)

References 33 publications

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“…These so-called truncated TrkB and TrkC isoforms have the potential to act as endogenous inhibitors of signaling by isoforms that possess tyrosine kinase domains (Eide et al, 1996). However, the truncated TrkB and TrkC isoforms also have the capacity to directly mediate neurotrophin-dependent signaling.…”

Section: The Neurotrophin Receptors: a Brief Summary Of Signaling Mecmentioning

confidence: 99%

Neurotrophin receptors: Old friends with new partners

Schecterson

Bothwell

2010

Developmental Neurobiology

113

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ABSTRACT:Neurotrophins are important regulators of embryonic development and adult function of most populations of neurons in vertebrate nervous systems. This signaling system regulates many diverse activities, including survival, axon outgrowth, and synaptic plasticity. In mammals, neurotrophin action is mediated by four receptors, p75 NTR , TrkA, TrkB, and TrkC. Although early studies viewed these receptors as solitary agents in the cells outer membrane, recent discoveries reveal that the cell outer membrane is a crowded and highly interactive neighborhood. Neurotrophin receptors partner with a diverse array of membrane proteins, dramatically expanding their functional repertoire. This review will focus on some of the most recent discoveries concerning the promiscuous partnering of neurotrophin receptors. '

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Section: The Neurotrophin Receptors: a Brief Summary Of Signaling Mecmentioning

confidence: 99%

Neurotrophin receptors: Old friends with new partners

Schecterson

Bothwell

2010

Developmental Neurobiology

113

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“…To investigate the role of TrkB signaling in cortical acuity in the mature animal we overexpressed a dominant negative TrkB.T1-EGFP fusion protein 19 in a large proportion of pyramidal cells after the maturation of cortical acuity. This was achieved by crossing mice carrying a Cre-dependent TrkB.T1-EGFP-transgene under the control of the Thy-1 promoter 16 with G35-3 Cre-recombinase transgenic animals 20 ( Supplementary Fig.…”

Section: Genetic Inhibition Of Trkb Signaling In the Adult Cortexmentioning

confidence: 99%

Contrast gain control and cortical TrkB signaling shape visual acuity

Heimel¹,

Saiepour²,

Chakravarthy³

et al. 2010

Nat Neurosci

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2The limits of visual acuity and contrast sensitivity are set by the eye, but what we perceive is determined by the visual cortex 1 . In healthy, mature people and animals, the visual acuities of the retina and the cortex are well-matched 2 , but this match is neither automatic nor unbreakable. Differences between cortical and retinal acuity are most apparent during development, when cortical acuity continues to rise after retinal development is completed 3 , and during aging, when behavioral acuity falls even without obvious changes in the eye or the thalamus 4 . Differences also occur as a result of cortical injury or erroneous development. This is the case with amblyopia, the most prevalent (2-4%) visual impairment in young people. Amblyopia is a reduced psychophysical acuity in one or both eyes. It is believed to be caused by deficient processing in the visual cortex 5 , but the mechanisms underlying the dissociations of retinal and cortical acuity in amblyopia and in the healthy aging and developing brain are unclear. Interestingly, there is a good match between changes in the cortical expression level of brain-derived neurotrophic factor (BDNF) and changes in visual acuity.During development, acuity and BDNF levels rise 6 , while both slowly decrease with age 4,7 . This relationship between BDNF and acuity also holds for experimentally induced amblyopia. BDNF mRNA and protein levels 8,9 and acuity 10 in the primary visual cortex (V1) responding to a monocularly deprived eye are all below normal. In amblyopic rats receiving environmental enrichment 11 or antidepressant treatment 12 , increased BDNF expression in the cortex was seen in parallel to the restoration of visual acuity. Moreover, transgenic mice overexpressing BDNF in the forebrain show a faster rise of cortical acuity 6 even when reared in darkness 13 . Although there is a wealth of data on the involvement of BDNF and its main receptor TrkB in neuronal development 14 , synaptic efficacy 15 , -morphology 16 and -plasticity 17,18 , it has remained unknown how BDNF promotes visual acuity at the coding level and whether BDNF signaling plays a role in acuity in the mature cortex. For these reasons we studied visual acuity in adult transgenic mice where, after normal development is completed, cortical TrkB/BDNF signaling is impaired. We found a loss of acuity, caused by a reduction in apparent contrast. Using a combination of experiments and modeling, we show the involvement of cortical gain control in the selective loss of responses to visual stimuli with high spatial frequencies and the maintenance of responses to low spatial frequencies. RESULTS Genetic inhibition of TrkB signaling in the adult cortexTo investigate the role of TrkB signaling in cortical acuity in the mature animal we overexpressed a dominant negative TrkB.T1-EGFP fusion protein 19 in a large proportion of pyramidal cells after the maturation of cortical acuity. This was achieved by crossing mice carrying a Cre-dependent TrkB.T1-EGFP-transgene under the control of the Thy-1 promoter ...

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“…The T1 isoform has dominant inhibitory effects on BDNF-mediated signaling, although the cellular and molecular functions of truncated TrkB isoforms are not well understood. [13][14][15][16] However, there is accumulating evidence that truncated TrkB isoforms have both dominant-negative inhibitory activity on full-length TrkB receptors and yet are capable of mediating signal transduction independent of full-length TrkB receptors. 14,15,17,18 Evidence supporting a role for BDNF signaling in mechanisms of alcohol and drug dependence has been well documented using different animal models.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

Anderson

Neyer

et al. 2007

Pharmacogenomics J

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To identify sequence variants in genes that may have roles in neuronal responses to alcohol, we resequenced the 5 0 region of tyrosine kinase B neurotrophin receptor gene (NTRK2) and determined linkage disequilibrium (LD) values, haplotype structure, and performed association analyses using 43 single nucleotide polymorphisms (SNPs) covering the entire NTRK2 region in a Finnish Caucasian sample of 229 alcohol-dependent subjects with antisocial personality disorder (ASPD) and 287 healthy controls. Individually, three SNPs were associated with alcohol dependence and alcohol abuse (AD) (P-value from 0.0019 to 0.0059, significance level was set at Pp0.01 corrected for multiple testing), whereas a common 18 locus haplotype within the largest LD block of NTRK2, a 119-kb region containing the 5 0 flanking region and exons 1-15, was marginally overrepresented in control subjects compared to AD individuals (global P ¼ 0.057). Taken together, these results support a role for the NTRK2 gene in addiction in a Caucasian population with AD and a subtype of ASPD.

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Naturally Occurring Truncated trkB Receptors Have Dominant Inhibitory Effects on Brain-Derived Neurotrophic Factor Signaling

Cited by 437 publications

References 33 publications

Neurotrophin receptors: Old friends with new partners

Neurotrophin receptors: Old friends with new partners

Contrast gain control and cortical TrkB signaling shape visual acuity

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

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