# The development of cortico-cerebellar circuits in a genetic form of intellectual disability

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $465,058

## Abstract

PROJECT SUMMARY
Intellectual disability (ID) is a prevalent neurodevelopmental disorder with no effective pharmacological
treatment. ID is often co-morbid with motor problems, and the nature of shared risk between these clinical
manifestations is not fully understood. Amongst the ID high-risk genes with significant motor involvement is the
X-linked gene DDX3X. Mutations in DDX3X affect almost exclusively females. DDX3X encodes an RNA
helicase regulating mRNA translation, and its role in neurodevelopment is just beginning to emerge. The
circuit-level changes induced by DDX3X mutations are unknown. There is a critical need to fill these gaps
because understanding the role of DDX3X in the formation of brain circuits might offer a new key to decipher
ID and its co-morbidity with motor problems. To address this unmet need, a mouse modeling DDX3X loss-of-
function mutations (Ddx3x+/-) was generated and characterized in our laboratory. The long-term goal is to map
the circuit-level drivers of ID and assess them as therapeutic targets. The overall objective is to examine the
role of DDX3X in shaping cortico-cerebellar circuits contributing to cognition and motor control. The central
hypothesis is that DDX3X regulates the development of cortico-cerebellar circuits subserving cognitive and
motor function. The rationale is that, once we understand the circuit-level drivers of ID, mechanism-based
precision therapeutics can be developed. The central hypothesis will be tested by pursuing two Specific Aims:
1) Identify the neural populations altered in the cerebellum of Ddx3x mutant mice; and, 2) Test the role of
cortico-cerebellar communication in behavioral deficits of Ddx3x mutant mice. Under Aim 1, the alterations in
cerebellar populations of Ddx3x+/- mice will be captured using single-cell RNA sequencing. The architecture of
the cerebellar cortex in Ddx3x+/- mice will be analyzed using immunostaining of cerebellar populations with
authenticated cell-specific markers during embryonic and postnatal life. The morphogenesis and
synaptogenesis of Ddx3x+/- Purkinje cells will be examined using single-embryo primary cultures. Under Aim 2,
the cortico-ponto-cerebellar pathway will be analyzed in Ddx3x+/- mice by simultaneously tracing cortico-pons
and ponto-cerebellar connections. Purkinje-specific Ddx3x+/- conditional mice will be generated and tested for
cognition and motor behavior using well-established behavioral paradigms. This proposal is innovative
because it will define the neurobiology of a largely unknown ID gene by mapping the cerebellar cells and
circuits affected by DDX3X mutations, and their relationship with behavior. It is also innovative because it
bridges developmental biology, cellular biology, behavioral neuroscience, and single-cell transcriptomics. The
application is significant because it will advance our understanding of ID and co-morbid motor deficits, and look
specifically at females, which have been neglected. It is also significant bec...

## Key facts

- **NIH application ID:** 10348976
- **Project number:** 1R21NS124928-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Silvia De Rubeis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,058
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348976

## Citation

> US National Institutes of Health, RePORTER application 10348976, The development of cortico-cerebellar circuits in a genetic form of intellectual disability (1R21NS124928-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10348976. Licensed CC0.

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