Mice lacking brain-derived neurotrophic factor develop with sensory deficits

DURING vertebrate development, neuronal survival depends on target-derived neurotrophic factors1,2. Brain-derived neurotrophic factor3 (BDNF), a member of the neurotrophin family, can prevent the death of particular peripheral sensory neurons in vitro4–6, and of central motor neurons as well as dopaminergic and cholinergic neurons of the basal forebrain during development7–9. It also prevents the death of motor neurons and midbrain dopaminergic neurons induced by lesions8,10–12. Here we show that mutant mice lacking BDNF have severe deficiencies in coordination and balance, associated with excessive degeneration in several sensory ganglia including the vestibular ganglion. The few remaining vestibular axons fail to contact the vestibular sensory epithelia, and terminate in the adjacent connective tissue. Survival of sympathetic, midbrain dopaminergic and motor neurons is not affected. These results indicate that BDNF is required for the survival and target innervation of particular neuronal populations.

[1]  M. Barbacid,et al.  Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death , 1993, Cell.

[2]  H. Thoenen,et al.  Purification of a new neurotrophic factor from mammalian brain. , 1982, The EMBO journal.

[3]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[4]  H. Thoenen,et al.  In vivo effect of brain‐derived neurotrophic factor on the survival of developing dorsal root ganglion cells. , 1987, The EMBO journal.

[5]  S. McMahon,et al.  Neurotrophins promote motor neuron survival and are present in embryonic limb bud , 1993, Nature.

[6]  R. Levi‐montalcini,et al.  The nerve growth factor 35 years later. , 1987, Science.

[7]  H. Thoenen,et al.  Placode and neural crest-derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor. , 1985, Developmental biology.

[8]  W. Snider,et al.  Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death , 1992, Nature.

[9]  B. Anderton,et al.  Monoclonal antibodies to mammalian neurofilaments , 1981, Bioscience reports.

[10]  Yves-Alain Barde,et al.  Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture , 1990, Neuron.

[11]  P. Ernfors,et al.  Cells Expressing mRNA for Neurotrophins and their Receptors During Embryonic Rat Development , 1992, The European journal of neuroscience.

[12]  Y. Li,et al.  Cultured hippocampal neurons show responses to BDNF, NT-3, and NT-4, but not NGF , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  R. Clatterbuck,et al.  Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo , 1993, Neuron.

[14]  Yves-Alain Barde,et al.  Trophic factors and neuronal survival , 1989, Neuron.

[15]  M. Avila,et al.  Brain-derived neurotrophic factor and neurotrophin-3 support the survival and neuritogenesis response of developing cochleovestibular ganglion neurons , 1993 .

[16]  M. Saarma,et al.  Brain-derived neurotrophic factor and neurotrophin 3 mRNAs in the peripheral target fields of developing inner ear ganglia. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[18]  H. Thoenen,et al.  Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section , 1992, Nature.

[19]  Y. Barde,et al.  Brain-derived neurotrophic factor prevents neuronal death in vivo , 1988, Nature.

[20]  R. McKay,et al.  Changes in neurotrophin responsiveness during the development of cerebellar granule neurons , 1992, Neuron.

[21]  R. Oppenheim,et al.  Brain-derived neurotrophic factor rescues developing avian motoneurons from cell death , 1992, Nature.

[22]  H. Thoenen,et al.  The response of chick sensory neurons to brain-derived neurotrophic factor , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.