# Role of Ankyrin-B in the Nervous System

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $64,343

## Abstract

SUMMARY (parent grant)
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.

## Key facts

- **NIH application ID:** 10351323
- **Project number:** 3R01NS110810-02S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Damaris N Lorenzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $64,343
- **Award type:** 3
- **Project period:** 2020-01-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10351323

## Citation

> US National Institutes of Health, RePORTER application 10351323, Role of Ankyrin-B in the Nervous System (3R01NS110810-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10351323. Licensed CC0.

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