Role of vascular endothelial growth factor and blood vessels in the development of GnRH neurons
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Data di Pubblicazione:
2008
Citazione:
Role of vascular endothelial growth factor and blood vessels in the development of GnRH
neurons / A. Cariboni, C. Ruhrberg, S. Rakic, K. Davidson, E. Dozio, R. Maggi, J.G. Parnavelas. ((Intervento presentato al convegno Neuroscience tenutosi a Washington, DC nel 2008.
Abstract:
Gonadotropin-releasing hormone (GnRH) neurons, a small number of cells scattered in the
hypothalamus, play an essential role in reproductive function. During development, these
neurons originate in the olfactory placode and migrate along olfactory/vomeronasal axons
in the nasal compartment to gain access into the forebrain and reach their final positions in
the hypothalamus. In humans, failure of GnRH neurons to migrate normally results in
delayed or absent pubertal maturation and infertility. The movement of these cells through
changing molecular environments suggests that numerous factors are involved in their
migration. We have recently described that classical neuronal guidance molecules, such
neuropilins (NRPs), are expressed by GnRH neurons, and established the importance of
NRP2 in their migration in vivo. Using immortalised GnRH cells (GN11), we also found that
two NRP ligands modulate their migratory response: the class 3 semaphorins (SEMA3A/3F)
and vascular endothelial growth factor A (VEGF). VEGF is a major regulator of
vasculogenesis and vascular permeability, interacting with receptor tyrosine kinases Flt-1
and Flk-1 on endothelial cells. Recent evidence indicates that VEGF has additional
non-vascular functions. In particular, the identification of NRPs as co-receptors for VEGF, as
well as the detection of their receptors on neurons, suggests that VEGF could act directly
on neurons to produce effects such survival and migration. In this study, the possible
interactions between VEGF, blood vessels and the GnRH-system have been tested. We first
visualized the presence of a network of blood vessels along peripherin-positive olfactory
axons and migrating GnRH neurons. In embryonic mice, blood vessels, stained with lectin
IsoB4, were seen around the olfactory placode, the vomeronasal organ, as well as in the
nasal mesenchyme, during the appearance and migration of GnRH neurons. Then, by using
RT-PCR and enzymatic staining of VEGF-LacZ reporter mice, we found that VEGF is
abundantly expressed in the developing olfactory structures. Moreover, FACS-isolated
embryonic GFP-GnRH neurons expressed specific transcripts for VEGF and its receptor
Flt-1. We found that GN11 cells-used as a model of migrating GnRH neurons- also express
these molecules and respond to VEGF. Functionally, we observed that the latter promotes
their survival and stimulates the chemomigration of GN11 cells by activating PI3K and
MAPK pathways. Taken together, these results indicate that GnRH neuron migration and
development are modulated by VEGF signalling, suggesting the existence of a ‘cross-talk’
between the vascular and GnRH-neuronal systems
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Keywords:
VEGF ; GnRH ; neuron ; migration ; fertility
Elenco autori:
A. Cariboni, C. Ruhrberg, S. Rakic, K. Davidson, E. Dozio, R. Maggi, J.G. Parnavelas
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