Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene

Smeyne, Richard J.; Klein, Rüdiger; Schnapp, Andreas; Long, Linda K.; Bryant, Sherri; Lewin, Anne; Lira, Sérgio A.; Barbacid, Mariano

doi:10.1038/368246a0

Cited by 921 publications

(608 citation statements)

References 18 publications

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“…30 This may explain why the level of TrkA, which correlates with spontaneous regression of neuroblastoma, is scored as a favorable prognosis marker. 31 On the other hand, considering the fact that TrkA is crucial for the development of sympathetic neuron, 32 one may argue how p53-null mice, which are deficient in p53 and consequently, may be low in TrkA, develop normally. 33 This does not necessarily contradict the observations in this study.…”

Section: Discussionmentioning

confidence: 99%

“…36 Specifically, a 176-bp fragment containing the GC-rich elements was amplified by PCR using pGL2/-1706 TrkA as template with 5 0 primer, TrkA-RE-5 (5 0 -CTC CTG GGC TTT CAG ACT TC-3 0 ), and 3 0 primer, TrkA-RE-3 (5 0 -CCC TAG TTG ACA GGC TAA ATA-3 0 ). The fragment was labeled with 32 P. Approximately 1 ng of the labeled probe DNA and 20 ng p53 protein were added to a mixture of 20 mM HEPES, pH 7.9, 25 mM KCl, 0.1 mM EDTA, 10% glycerol, 2 mM MgCl 2 , 2 mM spermidine, 0.5 mM DTT, 0.025% NP-40, 100 ng doublestraded poly(dG:dC), and 2 mg BSA. The p53 protein was expressed in a baculovirus expression system and affinity purified using anti-p53 monoclonal antibody PAb421.…”

Section: Gel-shift Assaymentioning

confidence: 99%

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p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

2006

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Abstractp53 is necessary for the elimination of neural cells inappropriately differentiated or in response to stimuli. However, the role of p53 in neuronal differentiation is not certain. Here, we showed that nerve growth factor (NGF)-mediated differentiation in PC12 cells is enhanced by overexpression of wild-type p53 but inhibited by mutant p53 or knockdown of endogenous wild-type p53, the latter of which can be rescued by expression of exogenous wild-type p53. Interestingly, p53 knockdown or overexpression of mutant p53 attenuates NGF-mediated activation of TrkA, the high-affinity receptor for NGF and a tyrosine kinase, and activation of the mitogen-activated protein kinase pathway. In addition, p53 knockdown reduces the constitutive levels of TrkA, which renders PC12 cells inert to NGF. And finally, we showed that both constitutive and stimuli-induced expressions of TrkA are regulated by p53 and that induction of TrkA by activated endogenous p53 enhances NGFmediated differentiation. Taken together, our data demonstrate that p53 plays a critical role in NGF-mediated neuronal differentiation in PC12 cells at least in part via regulation of TrkA levels.

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Section: Discussionmentioning

confidence: 99%

Section: Gel-shift Assaymentioning

confidence: 99%

p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

2006

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“…The TrkA τlacZ/τlacZ mice carry an insertion of tau-lacZ cDNA in the TrkA locus, and are a phenocopy of TrkA-null mice that lack 70-90% of sensory neurons (Fig. 2, Table 1 and data not shown) 8,11 . We focused our quantitative analysis on DRGs from the lumbar region (specifically L4 and L5, which contain well-studied ganglia that innervate the hindlimb).…”

Section: A Subset Of Trka-expressing Neurons Rescued In Trka Trkc/trkmentioning

confidence: 99%

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate

et al. 2004

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Tactile information is perceived by a heterogeneous population of specialized neurons. Neurotrophin receptors (the receptor tyrosine kinases, Trks) mark the major classes of these sensory neurons: TrkA is expressed in neurons that sense temperature and noxious stimuli, and TrkC is expressed in proprioceptive neurons that sense body position. Neurotrophin signaling through these receptors is required for cell survival. To test whether neurotrophins have an instructive role in sensory specification, we expressed rat TrkC from the TrkA (also known as Ntrk1) locus in mice. The surviving presumptive TrkA-expressing neurons adopted a proprioceptive phenotype, indicating that neurotrophin signaling can specify sensory neuron subtypes.Neurotrophins are well-characterized growth factors required for the survival of developing sensory neurons by signaling through a class of receptor tyrosine kinases 1-3 . The Trk receptors are specifically expressed in functionally distinct neurons of the dorsal root ganglia (DRG). TrkA, the receptor for nerve growth factor (NGF) is expressed in nociceptive and thermoceptive sensory neurons; TrkC, the high-affinity receptor for neurotrophin-3 (NT-3), is expressed in proprioceptive neurons; and TrkB, the receptor for brain-derived neurotrophic factor (BDNF) and NT-4, is expressed in less specifically characterized touch neurons. Each Trk receptor is required for the survival of the distinct class of neurons that it marks, consistent with a permissive role of neurotrophin signaling in neuronal survival. Various studies have suggested that Trk signaling is also involved in instructive steps of DRG development 4 . For example, neurotrophins are able to guide DRG axons in culture, and Bax -/-; TrkA -/-or Bax -/-;NT3 -/-DRG neurons, which are rescued from apoptosis by the lack of functional Bax protein, fail to develop properly 5-10 . To directly test whether signaling by a specific Trk can specify the subtype of DRG neurons in vivo, we designed a knock-in construct that expresses rat TrkC protein from the mouse TrkA locus while inactivating native TrkA expression. Table 2 and Fig. 4e-h).To further demonstrate that an effect on survival of existing proprioceptive neurons cannot account for the phenotype observed in TrkA TrkC/TrkC mice, we crossed the knock-in mice to Bax -/-mice. The deletion of Bax rescues DRG neurons from apoptosis, but does not cause the formation of extra proprioceptive neurons, as judged by the number of muscle spindles 10 (also compare parvalbumin and spindle counts in wild-type and Bax -/-mice; Tables 1 and 2). Notably, we observed a five-fold increase in parvalbumin-positive L5 DRGs and a seven-fold increase in muscle spindles in the soleus muscle of TrkA TrkC/TrkC ;Bax -/-mice when compared to Bax -/-mice ( Functional endogenous TrkC is required for the phenotypic switchIn an attempt to visualize the projection patterns of the ectopic proprioceptive neurons, we analyzed TrkA τlacZ/TrkC compound heterozygous mice. The TrkA-positive DRG neuronal projections are...

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“…Furthermore, TrkA knock-out mice show a 70 ± 90% reduction in the number of trigeminal neurones and similar losses in the sympathetic and dorsal root ganglia, probably due to a lack of survival signals resulting in a variety of sensory defects at P10. At P20 half of TrkA-de®cient mice are dead (Smeyne et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

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Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene

Cited by 921 publications

References 18 publications

p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate

Specific TrkA survival signals interfere with different apoptotic pathways

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