Regulation of the expression of BDNF and its receptors in the developing nervous system
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BDNF binds to two transmembrane receptors: trkB, which is a tyrosine kinase essential for signalling, and p75, which is a common neurotrophin receptor whose role is contoversial. To determine the relationship between BDNF synthesis, BDNF receptor expression, and neuronal responsiveness, the expression of BDNF, trkB, and p75 mRNAs were studied for different populations of sensory neurons whose axons reach their targets and become dependent on BDNF for survival at different times. BDNF mRNA was expressed in the peripheral and central targets of these neurons prior to the arrival of sensory axons. The onset of BDNF responsiveness was preceded by the expression of first p75 mRNA then trkB mRNA, and neurons that start responding to BDNF early were the first to express trkB mRNA. BDNF upregulated trkB mRNA expression just shortly before the onset of BDNF dependence. BDNF is expressed not only in sensory neuron targets but in some of these neurons themselves. To determine whether BDNF is synthesized in NGF-dependent or BDNF-dependent neurons, BDNF mRNA expression was studied in purified populations of cranial sensory neurons that depend on either NGF or BDNF for survival. During the period of neuronal death, BDNF mRNA expression was highest in NGF-dependent cutaneous sensory neurons, lower in BDNF-dependent cutaneous sensory neurons, and undetectable in BDNF-dependent proprioceptive neurons. In coculture, NGF-dependent neurons promoted the survival of BDNF-dependent neurons by the production and release of BDNF, implying a paracrine role for BDNF during the period of naturally occurring neuronal death. To determine if the level of p75 expression in sensory neurons is related to the particular neurotrophin they require for survival, p75 mRNA levels were measured in purified populations of cranial sensory neurons. No clear relationship between the level of p75 mRNA expression and neuron type was observed. Studies of the regulation of p75 mRNA expression in sympathetic neuroblasts revealed that retinoic acid increased and membrane depolarization using KCl decreased the levels of p75 mRNA.
Thesis, PhD Doctor of Philosophy
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