Stathmin/op18 modulates GnRH neurons migration

Stathmin is a ubiquitous, cytosolic phosphoprotein, which is involved in the control of microtubule dynamics and cell cycle progression. It is abundant in neurons with a peak of expression in the neonatal period although it remains highly expressed in the adult brain. In the present work, we investigated the cellular expression of stathmin in the GnRH system, in developing and adult mice, and we determined whether this expression is associated with an immature differentiation stage, as suggested by others. By double-immunohistochemistry, we show that immature migrating GnRH neurons specifically express stathmin. Indeed, stathmin expression level is high in GnRH neurons at embryonic stages, moderate in neonates and undetectable in fully differentiated hypothalamic GnRH neurons of the adult. These morphological in vivo results evoked an involvement for stathmin in the process of migration of GnRH neurons. To address this question we transfected the GnRH expressing cell line, GN-11, with stathmin sense and antisense expression vectors and subsequently analysed the migratory activity and differentiation state of transfectants. We found that GN-11 cells over expressing stathmin did show a significant increase in motility, a loss of aggregation capacity and a decrease in cadherins and N-CAM adhesion molecule expression. Conversely, in GN-11 cells transfected with the antisens stathmin vector, stathmin level of expression was strongly reduced and accompained by a reduced migratory response with respect to parental cells, an over expression of adhesion molecules, an induction of expression of markers for cell differentiation and synaptic activity, and the secretion of GnRH hormone into the culture medium. We show the in vivo expression of stathmin in immature GnRH neurons and the down regulation of stathmin expression in GN-11 cells is found to be sufficient to drive these cells toward a stationary and fully differentiated state. Supported by Compagnia di San Paolo.