# Contributions of the striatal direct pathway to the formation of corticofugal axon trajectories

> **NIH NIH F30** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $51,752

## Abstract

Project Summary/Abstract:
Abnormal striatal circuitry is implicated in the pathogenesis of common neurodevelopmental conditions including
autism spectrum disorder, tic disorder, attention-deficit/hyperactivity disorder, and obsessive-compulsive
disorder. The motor, cognitive, and social impairments characteristic of these disorders often interfere with an
individual’s ability to participate in activities of daily living. Despite the notion that defects in basal ganglia
connectivity can drive these behavioral impairments, the genetic and molecular origins of both normal and
pathologic neural circuits remain poorly understood, thereby limiting the rational development of therapeutics.
Sox8 is a transcription factor whose loss results in impaired striatal direct pathway outgrowth. Sox8 mutant mice
also appear to have defects in corticobulbar and corticospinal projections, despite that this gene is not expressed
in these cortical neurons. Given that these two axon pathways form in close proximity within the internal capsule
during early development, the anatomical defects present in Sox8 mutants thus suggest a novel role for the
direct pathway in the guidance of descending cortical projections. The central hypothesis for this application
is that direct pathway axons pioneer the forming internal capsule and guide descending corticobulbar
and corticospinal axons through the diencephalon and midbrain.
To test this hypothesis, Sox8 KO mice will be used as a tool to 1) interrogate the developmental requirement for
the direct pathway in guiding the appropriate outgrowth of descending corticofugal axons and 2) elucidate the
mechanism(s) by which it serves to guide them. Utilizing Sox8-EGFP (direct pathway) and Fezf2-TdTomato
(corticofugal pathway) BAC transgenic reporters to trace these pathways throughout development, Aim 1 will
focus on defining their developmental trajectories and determining their interdependence on one another for their
proper formation. The proposed experiments in Aim 2 will focus on establishing in vitro assays to identify
molecular regulators of direct and corticofugal pathway axon fasciculation and outgrowth. These assays will be
used to evaluate a candidate factor, Tenm2, in mediating the observed axon defects apparent in Sox8 mutants.
The successful completion of the aims outlined in this application will increase our understanding of how striatal
defects can impact the appropriate formation of other major axon tracts and thereby contribute to the etiology of
neurodevelopmental disorders

## Key facts

- **NIH application ID:** 10376754
- **Project number:** 5F30MH123056-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jacqueline Marie Ehrman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-06-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376754

## Citation

> US National Institutes of Health, RePORTER application 10376754, Contributions of the striatal direct pathway to the formation of corticofugal axon trajectories (5F30MH123056-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10376754. Licensed CC0.

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