Functions of Vti1a and Vti1b in the Development of the Mouse Nervous System: Evidence from Double Knockout Mice
2009
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.
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