# Hox-dependent mechanisms for establishment and maintenance of motor neuron terminal identity

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $411,324

## Abstract

Defects in motor neuron (MN) function or survival result in severe human pathologies, such as amyotrophic
lateral sclerosis and spinal muscular atrophy, with distinct MN subtypes differing in their susceptibility to
disease. There is currently no effective treatment for these disorders, in part due to a lack of understanding
of the molecular mechanisms that allow distinct MN subtypes to acquire and maintain their function-defining
properties. The continuous expression, from development through adulthood, of subtype-specific terminal
identity genes (e.g., genes coding for ion channels, neurotransmitter receptors, neuropeptides, signaling
molecules) defines the unique, functional features of a given MN subtype throughout life. How these genes
are induced and maintained is poorly understood. This proposal uses a novel approach to specifically focus
on the transcriptional regulation of MN subtype-specific terminal identity genes.
 The goal of this proposal is to uncover conserved, gene regulatory mechanisms that establish during
development, and maintain throughout life, the expression of MN subtype-specific terminal features. To this
end, this proposal combines the strengths of two model organisms: the nematode Caenorhabditis elegans
and mouse Mus musculus. By studying how C. elegans ventral nerve cord (VNC) MNs acquire their
subtype-specific features, we discovered a gene regulatory mechanism that involves the intersectional
activity of highly conserved transcription factors. We found that the transcription factor UNC-3 induces and
maintains the expression of terminal identity genes in all VNC MN subtypes. However, UNC-3 does not act
alone. It requires co-factors in the form of Hox proteins that act synergistically with UNC-3 to activate
expression of terminal identity genes in distinct MN subtypes along the anterior-posterior axis of the VNC.
We observed Hox expression in developing and adult MNs, suggesting that Hox proteins, similar to UNC-3,
not only induce, but also maintain expression of terminal identity genes. The unpublished data in this
application indicate that Hox proteins, in mice, also control expression of terminal identity genes in spinal
MNs, suggesting evolutionary conservation of our C. elegans findings. This proposal aims to uncover the
function of Hox proteins in adult C. elegans MNs (Aim 1), decipher the gene regulatory mechanisms
downstream of Hox in C. elegans MNs (Aim 2), and test the hypothesis that a mouse Hox protein (Hoxc8),
similar to its C. elegans orthologs, is required to induce and maintain expression of terminal identity genes
in MNs of the brachial spinal cord (Aim 3). Completion of the proposed activities will advance our
understanding of how distinct MN subtypes become and remain functional, which may provide new insights
into the etiology, diagnosis, and treatment of MN disorders.

## Key facts

- **NIH application ID:** 10123027
- **Project number:** 5R01NS116365-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Paschalis Kratsios
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,324
- **Award type:** 5
- **Project period:** 2020-03-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123027

## Citation

> US National Institutes of Health, RePORTER application 10123027, Hox-dependent mechanisms for establishment and maintenance of motor neuron terminal identity (5R01NS116365-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10123027. Licensed CC0.

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