Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene.
Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons in culture. In vivo, NGF decreases the extent of naturally occurring cell death in developing sympathetic ganglia and protects cholinergic neurons of the basal forebrain and caudatoputamen. NGF interacts with the low-affinity p75 receptor and with Trk, a receptor tyrosine kinase encoded by the trk proto-oncogene. To study the role of Trk in vivo, we have ablated the gene in embryonic stem cells by homologous recombination. Mice lacking Trk have severe sensory and sympathetic neuropathies and most die within one month of birth. They have extensive neuronal cell loss in trigeminal, sympathetic and dorsal root ganglia, as well as a decrease in the cholinergic basal forebrain projections to the hippocampus and cortex. These findings demonstrate that Trk is the primary mediator of the trophic actions of NGF in vivo and that this signalling pathway plays a crucial role in the development of both the peripheral and the central nervous systems.
Smeyne
R J
RJ
Department of Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Klein
R
R
Schnapp
A
A
Long
L K
LK
Bryant
S
S
Lewin
A
A
Lira
S A
SA
Barbacid
M
M
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology; D002452:Cell Count; D005727:Ganglia, Spinal / Q000473:pathology; D005728:Ganglia, Sympathetic / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism*; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells; D013564:Sympathetic Nervous System / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D012668:Trigeminal Ganglion / Q000473:pathology
D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D000110:Acetylcholinesterase