Migratory routing during postnatal hippocampal developmentcellular contributions and trafficking modulations

Resumo

There are two main neurogenic niches in the mammalian brain where neurogenesis perdures during all postnatal life: the subventricular zone in the lateral ventricles (SVZ) and the subgranular zone (SGZ) in the hippocampal dentate gyrus (DG) (Doetsch F et al., 1999; Alvarez-Buylla et al., 2002; Levison and Goldman 1993). This continuous neurogenesis is a complex process important for the maintenance and renewal of neurons inside the olfactory bulb (OB) and the DG circuitries, thus contributing to fundamental activities as brain plasticity and hippocampal-dependent memory (Alvarez-Buylla A. et al., 2000; Imayoshi I et al., 2008). Although postnatal migratory routes for new generated cells (i. e. the rostral migratory stream, RMS) are established since embryonic stages (Luskin MB 1993; Wichterle et al., 1999-2001; Laplagne et al., 2007), recent findings pointed out the existence of alternative routes of migration different from the classical ones and involving SVZ precursors and ventral brain caudal territories (De Marchis S et al., 2004; Seri B et al., 2006; Inta D et al., 2008). In particular, one of these alternative routes, the caudal migratory stream (CMS), is described as a novel embryonic route of migration in which interneurons move tangentially from the caudal ganglionic eminence (CGE) and are directed to the hippocampus (Yozu et al, 2005-Kanatani et al, 2008). However, the function and the role during the postnatal period of such dynamic cell movements remain still poorly understood. The correct coordination of the mechanisms underlying such cellular movements is a crucial key for the appropriate DG structural organization and the proper neural integration in the local network, a process that continues during postnatal stages (van Praag H et al., 2002). For this reason, we studied the identification of candidate molecules and signals implicated in the regulation of those mechanisms in the CMS during early postnatal life. To do that, we decided to analyze the developmental programme adopted from the postnatal brain for the maintenance of a high degree of structural plasticity permissive for neuronal replacing and/or remodeling to occur. Developmental signals in fact still persist even in the adult brain restricted to specific brain areas and participate as guidance cues conferring to migrating cells their intrinsic capacity to migrate. Among many guiding molecules implicated in tangential migration as the classical factors as Slits and Netrins (Nguyen-Ba-Charvet KT et al., 2004; Murase S et al., 2002), we found an interesting role also exerted by growth factors and morphogenetic proteins such as FGF signaling factors that were already described acting as guidance cues (Kuhn HG et al., 1997;Smith KM et al., 2006;Pombero A et al, 2010). In this work, we focused our attention on the postnatal persistence of caudal migratory routes of migration connecting the SVZ of the postnatal CGE (cSVZ) with the hippocampus. We combined ex vivo and in vivo techniques in which we differentially and specifically labeled cSVZ cells to follow their tangential migration caudally until the hippocampus. Immunohistochemical analysis revealed the neuronal charactestics of these caudal migratory cells and their ability to differentiate inside the pre-existing hippocampal neuronal network. Finally, we were able to demonstrate that the morphogene Fgf8 acts as a strong attractant molecule in this postnatal migration in vitro. Fgf8 signal exert a key role in attracting caudally cSVZ migrating cells operating trough its receptor FgFr1 and thus suggesting a model for this morphogenetic factor in postnatal migratory route establishment and control.