Neurothrophins during development : overexpression in neural stem cells

Sammanfattning: The neurotrophins constitute a family of secreted, diffusible peptide factors that are widely expressed in the developing nervous system. They are known to function as survival factors in the peripheral nervous system during the period of naturally occuring cell death, to promote axonal outgrowth and to affect neurotransmitter expression of responsive cells. Their function in the central nervous system remains to be elucidated, as does their role in target invasion and possible local chemotropic effect. We studied the mRNA expression of neurotrophin receptors in the brain during postnatal development. This study revealed a differentiated pattern of expression, indicating a role for neurotrophins in the development of the postnatal brain. Transgenic mice overexpressing the neurotrophin brain derived neurotrophic factor (BDNF) in the developing nervous system was then generated. The brains of these animals were grossly aberrant. When the brains of the BDNF overexpressing animals were analysed in parallel with brains of mice lacking the BDNF gene, it was revealed that BDNF acted on a population of early pioneer neurons in the neocortex. BDNF regulated their morphology and neuritogenes, as well as their expression of an extracellular matrix protein important for the migration and positioning of neocortical progenitor cells. Thus, BDNF is involved in brain maturation. Transgenic mice overexpressing either BDNF or a second neurotrophin family member, neurotrophin-3 (NT-3), in the nervous system and muscle during development, displayed phenotypic traits normally associated with transgenic mice lacking BDNF or NT-3. The unexpected phenotype turned out to be caused by a lack of peripheral target innervation. The projecting neuronal processes that entered fields of ectopic neurotrophin expression either stopped or changed direction, indicating that neurotrophins are important in target invasion and perhaps also in short distance chemotropic action. The expression of a marker of neural activity in the brain was investigated immediately before and after delivery in rats. The transition to the extrauterine environment increased neural activity in all areas of the brain within 30 minutes.