THESIS
2013
iv leaves, v-xx, 151 pages : illustrations (some color) ; 30 cm
Abstract
The cerebral cortex is the outermost layered structure of the cerebrum in humans and
some other vertebrates. It serves as the organization center of the brain and is involved in
memory, attention, thought, language, movement, and emotion. In humans, the cerebral cortex
comprises 6 layers, 2 to 4 mm thick and contains between 10 and 14 billion neurons. The radial
migration of newborn neurons is critical for cerebral cortex lamination. Proper neuronal
migration requires the precise and rapid reorganization of the actin and microtubule cytoskeleton.
However, the signaling mechanisms underlying these processes are not well understood. The
present study reveals that Mst3, a serine/threonine kinase highly expressed in the developing
mouse brain, is essential for neuronal migration and...[
Read more ]
The cerebral cortex is the outermost layered structure of the cerebrum in humans and
some other vertebrates. It serves as the organization center of the brain and is involved in
memory, attention, thought, language, movement, and emotion. In humans, the cerebral cortex
comprises 6 layers, 2 to 4 mm thick and contains between 10 and 14 billion neurons. The radial
migration of newborn neurons is critical for cerebral cortex lamination. Proper neuronal
migration requires the precise and rapid reorganization of the actin and microtubule cytoskeleton.
However, the signaling mechanisms underlying these processes are not well understood. The
present study reveals that Mst3, a serine/threonine kinase highly expressed in the developing
mouse brain, is essential for neuronal migration and final neuronal positioning in the developing
mouse neocortex. Mst3 silencing by in utero electroporation perturbs the multipolar–bipolar
transition of migrating neurons and significantly retards radial migration. The dendritic arborization as well as the upper cortical neurons excitability is also impaired in Mst3
knockdown neurons. The kinase activity of Mst3 is essential for its functions in neuronal
morphogenesis and migration, and is regulated via Ser79 phosphorylation by a serine/threonine
kinase, cyclin-dependent kinase 5 (Cdk5). Interestingly, Mst3 regulates neuronal migration by
modulating the activity of RhoA, a Rho GTPase critical for actin cytoskeletal reorganization.
The present results show that Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating
the GTPase activity of RhoA. Importantly, RhoA knockdown restores normal neuronal migration
in Mst3-knockdown cortices. These findings collectively indicate that Cdk5/Mst3 signaling
pathway regulates neuronal migration via RhoA-dependent actin dynamics. The convergence of
various kinase signaling pathways toward cytoskeletal organization and remodeling during
neuronal migration indicates that corticogenesis is precisely regulated by a complex and
coordinated signaling system.
Post a Comment