Role of Ankyrin-B in the Nervous System

The establishment of functional neuronal networks in the developing and adult central nervous system (CNS)
requires proper axonal specification, growth, branching, targeting, and synaptogenesis. Failure to appropriately
interconnect brain regions during development or to refine those connections during maturation can lead to
neurodevelopmental disabilities, such as autism, or to neurodegenerative and psychiatric disorders. De novo
mutations in ANK2, which encodes ankyrin-B (AnkB), have been identified in autism spectrum disorder (ASD)
patients, some of whom show aberrant axonal development. Neuronal loss of AnkB isoforms in mice results in
absence of long axonal projections in the CNS and an overall reduction in axonal length, confirming that AnkB
serves important roles in neuronal development in both humans and mice.
AnkB has two major isoforms in the brain; ubiquitously expressed 220kDa (AnkB220) and neuron-specific
440kDa AnkB (AnkB440). We recently discovered that AnkB220 is motile and promotes microtubule-based
axonal transport in cultured neurons to facilitate axonal growth. In contrast, AnkB440 interacts with cell adhesion
molecules implicated in axon guidance and synaptogenesis. Neurons lacking AnkB440 have increased axon
branching and synaptogenesis. We also found that AnkB is enriched at the postsynaptic density of glutamatergic
synapses. The different phenotypes of the isoform-specific knockout in mice highlights the specialized functions
of AnkB220 and AnkB440. Thus, there is a need to uncover the functional roles of neuronal AnkB and discern
the cellular specialization of its AnkB220 and AnkB440 isoforms.
Here, we will use novel mouse models lacking AnkB220 or AnkB440 in cortical neurons to unravel the precise
cellular mechanisms underlying the neuronal development and connectivity deficits caused by the loss of these
isoforms. Our research constitutes a novel effort to test our central hypothesis that AnkB coordinates neuronal
structural and functional connectivity through the combined and specific roles of the AnkB220 and AnkB440
isoforms. To achieve our goals, we aim to: (1) Determine if AnkB220-driven axonal transport is required for the
development and maintenance of long-range CNS axons in vivo; (2) Define molecular interactions required for
AnkB440-mediated regulation of synaptic connections during brain development; and (3) Define the roles of
AnkB in the postsynapse. Our studies will directly contribute to our understanding of the fundamental
mechanisms of axonal growth and synaptogenesis, thereby informing the pathophysiology of ankyrin-related
neurological and other brain disorders associated with deficits in white matter and synaptic connectivity.