# Differential Brain-Region Specific Roles of CASK in Optic Nerve Hypoplasia and Pontocerebellar Hypoplasia

> **NIH NIH F31** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $15,534

## Abstract

PROJECT SUMMARY
Understanding how different regions of the central nervous system (CNS) are affected by genetic insults is critical
to advancing the study of CNS pathologies which present a major public health burden in the United States. The
cerebellum and optic nerve are two such regions that are disproportionately hypoplastic in the majority of cases
of CASK gene mutation in humans. CASK is an enigmatic multi-domain scaffolding protein which plays a vital
role in organizing protein complexes at the pre-synapse through interactions with both active zone proteins and
trans-synaptic adhesion molecules such as liprins-α and neurexins. Mutations in the X-linked CASK gene in
humans are largely post-natally lethal in the hemizygous condition and result in microcephaly with pontine and
cerebellar hypoplasia (PCH) as well as optic nerve hypoplasia (ONH) in heterozygous mutations.
 While CASK has been traditionally regarded as playing a role in CNS development, recent data indicate
that it plays a continued role in the maintenance of the adult CNS. Specifically, acute global deletion of Cask in
adult mice using a CreER-Tamoxifen system leads to progressive degeneration in motor coordination
culminating in profound ataxia several months after tamoxifen injection. This coincides with a progressive
deterioration of cerebellar gross morphology. Thus, this presents a unique opportunity to understand the
continued role of a gene, previously regarded as developmentally important, in the function of the adult CNS and
how this function may differ in a region-specific manner.
 Recently, it has been demonstrated that progression of ONH in the context of CASK-loss is non-cell
autonomous in nature as deleting Cask from retinal ganglion cells themselves does not exacerbate ONH, but
deleting it from fibrous astrocytes of the optic nerve does exacerbate ONH. However, when Cask is deleted
specifically in granule cells (GCs) using a Calb2 promoter driven Cre recombinase, there appears to be a cell-
autonomous death of GCs. This provides an opportunity to examine how underlying etiopathology and functional
loss differ in two regions given the same genetic insult. As granule cells are the major excitatory driver of the
cerebellum, this project will investigate the progression of granule cell loss, the correlation of granule cell loss to
functional motor loss and ataxia, and the electrophysiological implications of loss of the major excitatory driver
in an isolated brain region. Further, the project will elucidate whether aberrations in spike-timing and frequency
among cerebellar Purkinje cells precede or follow anatomical reductions in granule cell number. The project will
also examine whether visual function correlates to optic nerve diameter in models which display ONH but not
PCH and vice versa using visual evoked potential recordings from V1 of visual cortex and the dorsal lateral
geniculate nucleus of the thalamus. Finally, the study will determine molecular mechanism...

## Key facts

- **NIH application ID:** 10427180
- **Project number:** 5F31NS120584-02
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Paras Patel
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $15,534
- **Award type:** 5
- **Project period:** 2021-04-13 → 2022-05-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427180

## Citation

> US National Institutes of Health, RePORTER application 10427180, Differential Brain-Region Specific Roles of CASK in Optic Nerve Hypoplasia and Pontocerebellar Hypoplasia (5F31NS120584-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10427180. Licensed CC0.

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