Functions of Vti1a and Vti1b in the Development of the Mouse Nervous System: Evidence from Double Knockout Mice

In eukaryotic cells molecules need to be transported to their correct intracellular destination without compromising the structural integrity of cellular compartments in order to maintain homoeostasis and to allow appropriate signalling cascades in certain space and time. To accomplish this, transport vesicles bud from an intracellular donor organelle and then target, dock and fuse with an acceptor organelle. SNARE (Soluble NSF attachment protein receptor) proteins have been implicated as central in membrane trafficking events. SNAREs vti1a and vti1b share 30% similarity in their amino acid sequences and have a distinct but overlapping subcellular localization. Vti1a has been associated with endosomal fusion and recycling processes after endocytosis whereas vti1b is connected with late endosomal fusion and lysosomal degradation events. Mice deficient of both endosomal SNARE proteins, vti1a and vti1b, die during intrauterine life just before birth, whereas single knockouts and triallelic mice survive and reach normal age without difficulty. These KO mice have various changes in central (CNS) as well as peripheral nervous system (PNS). In CNS they show wide ventricles and lack several fibre tracts including anterior commisure, hippocampal commisure, mammilothalamic, spinotrigeminal, corticospinal and pyramidal tracts. Corpus callosum thickness is greatly impaired in middle and thalamocortical axons cannot cross pallio-subpallial border. On the other hand only a few corticothalamic fibres can reach thalamus, overall data suggesting a deficit in membrane reorganization leading to impaired axon growth. Additionally, the KO mice also show alteration in cortical layering pattern. Layer 5 neurons are missing and layer 6 is expanded. This could be due to altered productivity in the ventricular zone during cortical layer development. The altered productivity may arise due to disturbances in cell polarity, failure in early decisions regarding lineage-specific differentiation from neural progenitors or any changes in signal ling molecules that could cause such consequences. On the other hand in PNS, KO mice show various degrees of neurodegeneration in different types of ganglia. Trigeminal (TG), dorsal root (DRG) and nodose-petrosal ganglia show severe neurodegeneration (up to 98%) whereas vestibular and cochlear ganglia show only 15-25% degeneration. This neurodegeneration may arise due to a lack of retrograde trafficking support during development of these ganglia or due to lack of delivering efficient plasma membrane required during axonal growth cone formation. Disparity in neurodegeneration among these ganglia could be due to the distance between the ganglia and their target. Unlike TG and DRG, vestibular and cochlear ganglia have less distant and therefore are able to survive. Overall phenotype suggests that vti1a and vti1b related endosomal functions are crucial for development of central as well as peripheral nervous system.