title: Severe sensory deficits but normal CNS development in newborn mice lacking TrkB and TrkC tyrosine protein kinase receptors.
abstract: Analysis of mice carrying targeted mutations in genes encoding neurotrophins and their signalling Trk receptors has provided critical information regarding the role that these molecules play in the mammalian nervous system. In this study we generated mice defective in both TrkB and TrkC tyrosine kinase receptors to determine the biological effects of these receptors in the absence of compensatory mechanisms. trkB(-/-);trkC(-/-) double-mutant mice were born at the expected frequency, indicating that TrkB and TrkC signalling are not required for embryonic survival. However, these double-mutant mice had a significantly shorter lifespan and displayed more severe sensory defects than their single-mutant trkB(-/-) and trkC(-/-) littermates. The most dramatic sensory deficit observed in trkB(-/-);trkC(-/-) mutant mice was the absence of vestibular and cochlear ganglia. Interestingly, these mice developed inner ear sensory epithelia in spite of the complete absence of sensory innervation. Analysis of the CNS in trkB(-/-);trkC(-/-) mutant mice revealed a well formed hippocampus, cortex and thalamus. Moreover, the pattern of expression of several neuronal markers appeared normal in these animals. These observations suggest that neurotrophin signalling through TrkB and TrkC receptors is essential for the development of sensory ganglia; however, it does not play a major role in the differentiation and survival of CNS neurons during embryonic development.
authors.affiliation: Department of Molecular Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: I
authors.initials: I
authors.lastname: Silos-Santiago
authors.forename: A M
authors.initials: AM
authors.lastname: Fagan
authors.forename: M
authors.initials: M
authors.lastname: Garber
authors.forename: B
authors.initials: B
authors.lastname: Fritzsch
authors.forename: M
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002454:Cell Differentiation; D002470:Cell Survival; D003051:Cochlea / Q000166:cytology / Q000473:pathology / Q000502:physiology; D003433:Crosses, Genetic; D007758:Ear, Inner / Q000502:physiology; D005314:Embryonic and Fetal Development; D004847:Epithelial Cells / Q000502:physiology; D017950:Ganglia, Sensory / Q000254:growth & development / Q000502:physiology*; D005829:Geniculate Bodies / Q000002:abnormalities / Q000473:pathology*; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D010320:Parvalbumins / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D020801:Receptor, Ciliary Neurotrophic Factor; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D014722:Vestibule, Labyrinth / Q000166:cytology / Q000473:pathology / Q000502:physiology
chemical_list: D064026:Calbindins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D064030:S100 Calcium Binding Protein G; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC