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

  title={Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene},
  author={Richard J Smeyne and R{\"u}diger Klein and Andreas Schnapp and Linda K. Long and Sherri Bryant and Anne C. Lewin and Sergio A. Lira and Mariano Barbacid},
NERVE growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons in culture1,2. In vivo, NGF decreases the extent of naturally occurring cell death in developing sympathetic ganglia and protects cholinergic neurons of the basal forebrain and caudatoputamen1-3. NGF interacts with the low-affinity p75 receptor and with Trk, a receptor tyrosine kinase encoded by the trk proto-oncogene4,5. To study the role of Trk in vivo, we have ablated the… 
Comparison of target innervation by sympathetic axons in adult wild type and heterozygous mice for nerve growth factor or its receptor trkA
Findings reveal that while levels of trkA are reduced in SCG neurons of adult NGF+/− and trk/− mice (compared with their wild type counterparts), sympathetic axons are capable of achieving normal patterns of target innervation intrkA+/+ mice but not in NGF+.
A Role for TrkA during Maturation of Striatal and Basal Forebrain Cholinergic Neurons In Vivo
The data suggest that, in the absence of NGF/TrkA signaling, striatal cholinergic neurons and BFCNs do not mature fully and that B FCNs begin to atrophy and/or die surrounding the time of target innervation.
In vivo function of NGF/TrkA signaling in the cholinergic neurons of the murine basal forebrain
This model demonstrates that NGF/TrkA signaling is essential for the cholinergic differentiation of many neurons in the basal forebrain and modulates the processing of the amyloid precursor protein APP in theBasal forebrain.
Synchronous Onset of NGF and TrkA Survival Dependence in Developing Dorsal Root Ganglia
It is concluded that many murine DRG cells require NT-3 for survival before exhibiting NGF dependence and thatNT-3 activation of TrkA is unimportant to these early NT- 3 survival-promoting actions.
Severe sensory and sympathetic deficits in mice lacking neurotrophin-3
It is reported that mice lacking neurotrophin-3 have severe deficits in sensory and sympathetic populations and motor neurons, the enteric nervous system, and the major anatomical regions of the central nervous system seem to develop normally.
Neurotrophin-3 promotes the cholinergic differentiation of sympathetic neurons.
A role for NT3 as a differentiation factor for cholinergic neurons is suggested and a link between neurotrophins and neurotransmitter plasticity is established in the vertebrate nervous system.
Loss of NGF-TrkA Signaling from the CNS Is Not Sufficient to Induce Cognitive Impairments in Young Adult or Intermediate-Aged Mice
It is confirmed that NGF-TrkA signaling supports survival of only a small proportion of cholinergic neurons during development; however, this signaling is not required for trophic support or connectivity of the remaining basal forebrain cholin allergic neurons.
TrkA Gene Ablation in Basal Forebrain Results in Dysfunction of the Cholinergic Circuitry
It is demonstrated that the normal developmental increase of choline acetyltransferase expression becomes critically dependent on TrkA signaling before neuronal connections are established and results in cholinergic BF dysfunction and cognitive decline that is reminiscent of MCI and early AD.


Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements
It is shown that homozygous mice defective for TrkC tyrosine protein kinase receptors lack la muscle afferent projections to spinal motor neurons and have fewer large myelinated axons in the dorsal root and posterior columns of the spinal cord, indicating that NT3/TrkC-dependent sensory neurons may play a primary role in proprioception, the sense of position and movement of the limbs.
Expression of the trk proto-oncogene is restricted to the sensory cranial and spinal ganglia of neural crest origin in mouse development.
The data show that trk, a gene associated with malignancy in humans, is a specific marker for a set of neural crest-derived sensory neurons, and are consistent with the hypothesis that this proto-oncogene may have an important role in the development or phenotype of the neurons where it is expressed.
Neurotrophin receptor genes are expressed in distinct patterns in developing dorsal root ganglia
It is shown that neurotrophin receptors are expressed in thoracic and lumbar DRGs by embryonic day 13 (E13), which is only 24–48 hr after neurogenesis begins in these ganglia, and trk expression occurs in a time frame consistent with the idea that trks mediate responses of DRG neurons to neurotrophins that are synthesized in both the periphery and spinal cord at early developmental stages.
trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues.
Insight is provided into the role of Trk-family receptors and nerve growth factor-related neurotrophins during development and suggest that, in addition to regulating neuronal survival and differentiation, the neurotrophin/Trk receptor system may have broader physiological effects.
Effects of nerve growth factor on cholinergic brain neurons.
  • C. Dreyfus
  • Biology
    Trends in pharmacological sciences
  • 1989