# Gene regulatory mechanisms controlling development of serotonin neuron subtypes

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $596,338

## Abstract

Although significant progress has been made in understanding the genetic origins of
neurodevelopmental disorders, it remains unclear what specific molecular steps are disrupted and in which
specific neurons types they are dysfunctional or inoperable. One potential reason for this lack of understanding
is that neurons, originally classified according the type of transmitter produced, are now well known to possess
substantial molecular, cellular, and functional heterogeneity. It seems plausible that neurodevelopmental
disorders may arise not only from developmentally altered identities of an entire population of one particular
neuron type but also from altered development of one of its specific molecular or functional subtype(s). There
has been a decades-long intense interest in the regulatory mechanisms controlling 5-HT neurons as 5-HT has
wide-ranging modulatory effects on central neural circuitry and dysfunction of the serotonergic system has
been implicated in several neuropsychiatric diseases including depression, stress-related anxiety disorders,
autism, intellectual disability, OCD, and schizophrenia. 5-HT neurons possess tremendous molecular,
morphological, and electrophysiological heterogeneity. However, developmental trajectories of 5-HT neuron
subtypes are currently unknown as are the regulatory mechanisms that govern their development. The
objective of the proposed research is to use single cell RNA-seq and single cell ATAC-seq to comprehensively
define the spatiotemporal developmental trajectories of 5-HT neuron subtype transcriptomes and chromatin
accessibility. We will combine recent advances in single-cell genomics methods together with our well-
established serotonergic transgenic tools, our extensive experience in flow sorting mouse 5-HT neurons, and
our bioinformatics expertise to investigate the development of single-cell 5-HT neuron transcriptomes and
chromatin accessibility throughout fetal to early postnatal maturation. We will also investigate at the single cell
level, the hypothesis that the two disease-associated terminal selectors in 5-HT neurons, Pet1 and Lmx1b,
function to determine postmitotic 5-HT neuron subtypes through differential regulation of subtype-specific gene
expression, subtype-specific chromatin accessibility and control of downstream subtype-specific transcription
factor codes. Pet1 is of special interest as homozygous knockout mutations in FEV, the human ortholog of
Pet1, were recently reported in two brothers with Intellectual Disability and Autism Spectrum Disorder. In Aim
1, we will define the developmental trajectories of 5-HT neuron subtypes. In Aim 2, we will investigate the
control of 5-HT neuron subtype transcriptomes by Pet1 and Lmx1b. In Aim 3, we will determine the chromatin
mechanisms involved in the generation of 5-HT neuron subtypes. The completion of our proposed aims will
lead to a greater understanding of the subtype-specific gene regulatory networks that generate 5-HT neuron
subtypes, w...

## Key facts

- **NIH application ID:** 10363390
- **Project number:** 1R01MH125918-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** EVAN S DENERIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $596,338
- **Award type:** 1
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363390

## Citation

> US National Institutes of Health, RePORTER application 10363390, Gene regulatory mechanisms controlling development of serotonin neuron subtypes (1R01MH125918-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10363390. Licensed CC0.

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