Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Germana Dalmasso “Role of BDNF on SVZ neuroblast migration in the postnatal mouse brain” The central nervous system of higher vertebrates has been considered for a long time to be incapable of cell renewal during adulthood. This view, however, was challenged over 40 years ago when Joseph Altman demonstrated the presence of adult-generated neurons within some brain areas of adult vertebrates1. The occurrence of newborn neurons in the adult brain has been described in every major mammalian group in which it has been studied, indicating that adult neurogenesis is a highly conserved feature among mammals. Active neurogenesis is principally located in two restricted regions of the adult mammalian brain: the hippocampal dentate gyrus and the olfactory bulb (OB)2. Especially the olfactory system offers unique opportunities to investigate neuronal birth, migration, and differentiation, processes involving a complex interplay between genetic and epigenetic influences. Newly formed cells of the OB are generated from multipotent neuronal progenitor cells residing in the adult subventricular zone (SVZ) of the lateral ventricles and in its rostral extension. The progeny of these cells migrate along the rostral migratory stream, wherein migrating cells form chains enwrapped by a particular type of astrocytes, called glial tubes. Migrating cells reach the core of the OB, where they turn to move radially out of the SVZ into the granular and glomerular layers and differentiate into interneurons3. Several studies have demonstrated that specific steps of this process are dynamically regulated by diverse molecular and environmental factors. The brain-derived neurotrophic factor (BDNF) has been so far correlated with survival4 and differentiation5 of the newly generated cells in the SVZ system. Moreover, recent findings suggest a role for BDNF in the control of cellular migration both on cerebellar granule cells6 and on cortical interneurons during development7. These evidence drove us to investigate the potential involvement of this neurotrophin in the process of SVZ-neuroblast migration. In the present thesis the expression of the transcripts and proteins for BDNF and its high affinity receptor TrkB along the migratory pathway in the SVZ system is described. The distribution of TrkB receptor has been analyzed by double immunolabelling reactions on coronal sections at the different levels of the SVZ system and it’s demonstrated to be expressed by SVZ migrating neuroblasts, positively marked for PSA-NCAM. Culturing SVZ tissue explants in a matrigel three-dimensional matrix in vitro, we show that treatment of the explants with BDNF for 24hrs produces a significant increase in the area of migration. BDNF-induced migration is blocked after treatment with the TrkB receptor tyrosine kinase inhibitor K252a, suggesting a motogenic effect of this neurotrophin acting through activation of TrkB receptors on SVZ precursors. We have also verified the hypothesis of a role for BDNF in chemoattraction on SVZ neuroblast using the in vitro Boyden chamber assay. The results obtained show that the neurotrophin is capable to induce a directional migratory response, on precursors isolated from the SVZ system. To further elucidate the function of BDNF on neuronal migration, we have analyzed the downstream signalling events activated by the neurotrophin in SVZ precursor cells. We show that PI3K and MAPK transduction pathways are both required for BDNF induced cell migration. The present results support a novel functional implication of BDNF in the regulation of neuroblast migration in the SVZ system. References: 1 Altman J., (1969) J. Comp. Neurol. 137:433-457. Lois C., (1994) Science 264:1145-1148. 3 Abrous D.N., (2005) Physiological Reviews 85:523-569. 4 Leventhal C., (1999) Molecular and Cellular Neuroscience 13:450–464. 2 5 Gascon E., (2005) Eur. J. Neurosci. 21:69-80. Borghesani P.R., (2002) Development 129:1435-1442. 7 Behar T.N., (1997) Eur. J. Neurosci. 9:2561-2570. 6