| Abstract |
During central nervous system (CNS) development a plurality of intracellular and extracellular molecules plays crucial role in the organization and coordination of different neuronal populations. Cell adhesion molecules (cell adhesion molecules, CAMs), as key members of extracellular molecules, are known to participate in the communication of neurons inside CNS. The contacts created by CAMs are between neurons as well as between neurons and supporting cells (glial cells). Moreover CAMs participates in neurons communication with their environment, by creating contacts with extracellular matrix molecules. The developmental activities integrated by CAMs through the above contacts are neuronal migration, the elongation and guidance of axons, the creation of synapses and the fasciculation of nerve fibers. The role of CAMs in the development of sensory systems is well studied mainly in the optical and olfactory system.
In the first part of current thesis we studied the role of CAM TAG-1, in the development and organization of projection neurons in the olfactory bulb (OB). It is well known how the olfactory sensory neurons and their axons from the olfactory epithelium (OE) are organized according to the olfactory receptors expressed on their surface. The above organization pattern plays a role in the correct synapses formation at the level of glomeruli (GL) in OB forming the olfactory receptor map (ORM). However the way in which the major projection neurons of the OB, mitral cells (MCs), are organized during the development to receive information from specific GL is still elusive. In current study we have shown that TAG-1 is crucial for the proper distribution and guidance of developing MCs, specifically those born in developmental stage E11,5. When it is absent the MCs (E11,5) do not occupy the correct positions inside the main olfactory bulb (MOB), but remain within areas of accessory olfactory bulb (AOB) until adulthood. The above mentioned defects results in changes of neuronal activation profile of both MOB and the primary olfactory cortex (piriform cortex, PC), but not the AOB. These developmental disorders influence the olfactory ability of the TAG-1 mutant mice. As a result they present reduced long-term olfactory social memory and impaired olfactory recognition and discrimination abilities. Furthermore we created a database and highlighted specific molecules that can be used as olfactory system cell subpopulations special markers (from E11,5-P56). The above data could be useful in future studies related with the olfactory system development. Through the second part of this work we tried to elucidate the role of a subset of vestibular axons, the primary vestibular fibers (primary vestibular fibers, PVFs), in the development and organization of the cerebellum. It is known from previous studies in rat that PVF enters the cerebellum as early as E11,5 and constitute the first afferent fibers during development. In the next developmental stages fasciculated PVFs, occupy a large area in the cerebellum as they travel to more posterior regions of the tissue. Previous studies have clearly highlighted that the role of PVF is not to act as a scaffold in the course of subsequent afferents fibers in the cerebellum. In addition PVFs does not act as guidance organizers in granular cell migration (GCs) from external granular layer (EGL) to their end positions.
In the second part of the current study we presented that PVF enters inside the cerebellar primordium in developmental stage E11,5 (as in rats) .Later on we showed that the axons of PVFs co-fasciculates (at E13,5) with the CalB+ Purkinje cell (PCs) axons. More over for first time we shown that the axonal bundles of CalB + PCs follow the course of PVFs bundles and exits outside the cerebellum through the inferior cerebellar peduncle (ICP), toward the vestibular nuclei (VN). Furthermore in Six1- / - animals where PVFs never generates, the CalB+ PCs axons presents severe fasciculation deficits (hyper-fasciculation) as well as defects in axonal orientation inside the cerebellum. As the above PCs axons follow diverse disorganized directions within the tissue, a small proportion succeeds to exits the cerebellum through restiform body (RB) and not through ICP. In this pathway L1 is expressed, as it is expressed on PVFs and PCs axons. From the CAMs that we checked and was expressed in the pathway of PVFs only the absence of L1 led to defects in fasciculation (small bundles) and orientation of PCs axons, that never exits the cerebellum properly. In conclusion we presented that L1 CAM is possible a key molecule in PVFs actions as cellular scaffold and fasciculation organizer of Calb+ PCs axons. Through this role it helps PCs axons to be well oriented inside the cerebellum and exits through ICP toward VNs.
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Μελέτη των ενδοκυττάριων και εξωκυττάριων μηνυματοδοτικών μορίων στην ανάπτυξη και την οργάνωση των αισθητήριων συστημάτων και του εγκεφαλικού φλοιού
