# Development and function of hypothalamic Lhx6-positive neurons

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

Project Summary
 GABAergic neurons of the dorsolateral hypothalamus play an essential role in both the regulating the
sleep/wake cycle, but little is known about the molecular mechanisms that control their development. We have
recently found that the LIM homeodomain transcription factor Lhx6 is necessary for development of a population
of sleep-promoting GABAergic neurons in the zona incerta in the hypothalamus. Lhx6 is essential for
development and migration of most telencephalic interneurons, in the hypothalamus Lhx6 is expressed in a much
more restricted subset of neurons that do not express markers of telencephalic Lhx6-positive interneurons. The
role of Lhx6 in development of telencephalic and hypothalamic neurons differs in several important respects.
Lhx6 expression is regulated by different transcription factors in the two regions. Preliminary gene expression
analysis has identified a number of genes that are strong candidates for mediating these differences. In this
proposal, we aim to identify the molecular mechanisms that guide the specification and survival of hypothalamic
Lhx6 neurons. First, we will use a combination of genetic approaches to identify transcriptional regulatory
networks that are required for initiation and maintenance of hypothalamic expression of Lhx6, and that control
development of distinct subtypes of Lhx6-positive neurons. Next, we will determine whether tangential cell
migration plays a critical role in the localization of sleep-promoting Lhx6-positive neurons, and identify the
molecular mechanisms that control this process. Finally, we will identify molecular subtypes of sleep-activated
Lhx6-positive hypothalamic neurons, and investigate how mutants that disrupt the development of these neurons
result in altered regulation of the sleep/wake cycle. This will provide insight into molecular pathways that control
the assembly of key components of hypothalamic neural circuitry, and may identify therapeutic targets for
treatment of sleep disorders.

## Key facts

- **NIH application ID:** 10372173
- **Project number:** 5R01MH126676-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Seth Blackshaw
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2021-03-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372173

## Citation

> US National Institutes of Health, RePORTER application 10372173, Development and function of hypothalamic Lhx6-positive neurons (5R01MH126676-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372173. Licensed CC0.

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