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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