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Principal Investigator: Seth Blackshaw
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $409,375
Funding agency: National Institute of Mental Health
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.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Anterior><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cellular Migration><Cellular Motility><Connector Neuron><Defect><Development><Elements><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic analyses><Genetic study><Homeo Domain><Homeostasis><Hypothalamic structure><Hypothalamus><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Maintenance><Mediating><Molecular><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Pathway interactions><Physiological Homeostasis><Play><Population><Posterior Hypothalamic Region><Posterior Hypothalamus><Process><Regulatory Element><Role><Signal Transduction><Signal Transduction Systems><Signaling><Sleep><Sleep Disorders><Sleep Wake Cycle><Specific qualifier value><Specified><Testing><Transcript Expression Analyses><Transcript Expression Analysis><Transcription Factor Proto-Oncogene><Transcription factor genes><Work><analyze gene expression><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological signal transduction><cell motility><developmental><experiment><experimental research><experimental study><experiments><expression subtypes><gene expression analysis><gene expression assay><genetic analysis><genetic approach><genetic strategy><homeodomain><hypothalamic><inhibitory neuron><insight><migration><molecular sub-types><molecular subsets><molecular subtypes><mutant><neural circuit><neural circuitry><neurocircuitry><neuron development><neuronal><neuronal development><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><pressure><selective expression><selectively expressed><sleep control><sleep diseases><sleep dysfunction><sleep illness><sleep problem><sleep regulation><social role><synaptic circuit><synaptic circuitry><therapeutic target><transcription factor><transcription regulatory network><transcriptional profiling><zona incerta>