# Role of autism-linked genes in developmental refinement of the corpus callosum

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $437,500

## Abstract

The corpus callosum (CC) provides interhemispheric communication essential for cognitive and associative
processes, with critical roles in several higher order functions including sensory processing, motor coordination,
and language acquisition and formation. Malformation of the CC has devastating functional consequences;
agenesis and hypoplasia of the CC is linked to several conditions associated with severe neurological and
cognitive disabilities. In addition, anatomical and physiological deficits of the CC also have been commonly
reported in several neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). Yet, the cellular
and molecular mechanisms involved with the malformation of the CC in these disorders remain undefined. Our
current understanding of CC development is exclusively limited to factors and mechanisms involved with the
early axon guidance phase, as well as those involved with the later myelination and synaptogenesis stages.
However, the regulation of early postnatal CC refinement, in which initially produced callosal axons are
selectively preserved or eliminated, remains completely unknown and is vastly understudied. Our major goal is
to elucidate the mechanisms underlying the critical but vastly unexplored early postnatal processes
governing CC development. This understanding will be crucial in shedding light on the pathogenesis of callosal
abnormalities in neurodevelopmental disorders. Along with axon elimination, axon preservation is critical in
maintaining the appropriate neuronal connections during this developmental refinement period, which leaves a
lasting impact throughout the life of the organism. Our preliminary investigation has led to us to an intriguing
hypothesis that the autism-linked gene, Plexin-A4, selectively preserves a subset of callosal axons during early
postnatal CC refinement via the inhibition of caspase-mediated tubulin cleavage. In this proposed project, we
will first establish the as-of-yet unconfirmed developmental elimination of callosal axons in the mouse CC (Aim
1). We will then test our hypothesis using various genetic and molecular biological techniques through our mouse
model of CC refinement (Aim 2). We will then define molecular links between Plexin-A4 and caspase inhibition,
a relationship which has previously been unknown, as well as identify novel autism-linked genes that are
essential in the postnatal maintenance/elimination of callosal axons, using a unique combination of mass
spectrometry and single-cell RNA sequencing (Aim 3). These results will, for the first time, validate the use of a
mouse model to study the fundamental process of axon preservation during the postnatal refinement of the CC,
and identify molecular pathways critical for this process. This novel study will also provide avenues for
deciphering mechanisms underlying abnormal CC formation implicated in functional deficits associated with ASD
and other neurodevelopmental disorders. Our results will open new a...

## Key facts

- **NIH application ID:** 9917831
- **Project number:** 5R01MH111674-04
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Masaaki Torii
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917831

## Citation

> US National Institutes of Health, RePORTER application 9917831, Role of autism-linked genes in developmental refinement of the corpus callosum (5R01MH111674-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9917831. Licensed CC0.

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