# Cerebellar hypoplasia and chromosome elimination in mouse models of Down syndrome

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary/Abstract
Cerebellar hypoplasia may contribute to syndrome-specific cognitive and adaptive deficits in Down syndrome,
which affects more than a quarter million individuals in the United States. The Ts65Dn mouse model of Down
syndrome reflects several important cerebellar phenotypes observed in individuals with Down syndrome,
including reduced total volume and reduced granule cell density. During development of the cerebellar cortex,
granule cell precursors proliferate in response to the mitogen Sonic hedgehog. Granule cell precursors isolated
from Ts65Dn mice proliferate less than control cells when treated with Sonic hedgehog, and a single dose of
the Sonic hedgehog agonist, SAG, on the first day after birth rescues cerebellar morphology and some
learning deficits in Ts65Dn mice. However, it is unknown which trisomic genes contribute to inhibition of Sonic
hedgehog-dependent proliferation. Understanding how trisomy causes cerebellar hypoplasia and other
developmental phenotypes is critical to establishing tractable drug targets for ameliorating Down syndrome-
associated cognitive deficits. Therefore, we hypothesize that the overexpression of specific trisomic genes
negatively regulates the endogenous Sonic hedgehog pathway during cerebellar development. We will
address this hypothesis by overexpressing human chromosome 21 genes in a series of in vitro screens to
identify candidates that inhibit Sonic hedgehog signaling. Candidates that are identified in these screens and
are expressed in the developing cerebellum will be overexpressed in primary granule cell precursors. We will
also optimize a technique for CRISPR/Cas9-mediated chromosome elimination in aneuploid cell lines derived
from a mouse model of Down syndrome. Inducible chromosome elimination in a mouse model of Down
syndrome would provide a method for detecting the developmental origins of phenotypes caused by trisomy.
Together, successful completion of this project will yield new insights into how overexpression of human
chromosome 21 genes dampen response to Sonic hedgehog during cerebellar development and will produce
a powerful tool for identifying how dosage imbalance acts to produce phenotypes in Down syndrome.

## Key facts

- **NIH application ID:** 10017057
- **Project number:** 5F31HD098826-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Anna Joyce Moyer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-17 → 2022-07-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017057

## Citation

> US National Institutes of Health, RePORTER application 10017057, Cerebellar hypoplasia and chromosome elimination in mouse models of Down syndrome (5F31HD098826-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10017057. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*