THESIS
2020
xi, 78 pages : color illustrations ; 30 cm
Abstract
The 440 kDa splicing variant of ankyrin B (gAnkB) is the predominantly
expressed ankyrin B isoform during early brain development. It is only expressed in
neurons and specifically distributed along unmyelinated axons beneath axonal plasma
membranes. gAnkB is derived by acquiring a giant insertion region, which is encoded
by a single giant exon. The giant insertion is over 2,000-residue-long, predicted to be
intrinsically disordered and with hitherto poorly understood functions. ANK2, the
encoding gene of ankyrin B, has been identified as one of the top high-risk
autism-related genes. Human-patient-mimic autistic mouse model studies revealed
that gAnkB deficiency leads to increased stochastic connectivity in the brain and
enhanced axon branching in cultured neurons, but with an...[
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The 440 kDa splicing variant of ankyrin B (gAnkB) is the predominantly
expressed ankyrin B isoform during early brain development. It is only expressed in
neurons and specifically distributed along unmyelinated axons beneath axonal plasma
membranes. gAnkB is derived by acquiring a giant insertion region, which is encoded
by a single giant exon. The giant insertion is over 2,000-residue-long, predicted to be
intrinsically disordered and with hitherto poorly understood functions. ANK2, the
encoding gene of ankyrin B, has been identified as one of the top high-risk
autism-related genes. Human-patient-mimic autistic mouse model studies revealed
that gAnkB deficiency leads to increased stochastic connectivity in the brain and
enhanced axon branching in cultured neurons, but with an unknown underlying
molecular mechanism. Here we discovered that cultured neurons from transgenic
mice, with their giant exon of ANK2 specifically removed, displayed increased stochastic collateral axon branching. Also, axonal microtubule stability in these
neurons decreased, with more microtubules deviating from the axonal shaft and
invading into axonal filopodia. A region from the giant insertion of gAnkB containing
15-repeat was identified to be essential for direct microtubule binding and bundling
both in vitro and in living cells. A gAnkB mutant, which is defective in microtubule
binding and bundling due to point mutations in the 15-repeat sequence, is totally
incapable of suppressing collateral axon branching in cultured gAnkB-deficient
neurons. Taken together, gAnkB may play a critical role in stabilizing the physical
and topological structures of neuronal axons by stabilizing microtubules via its
insertion.
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