Dopamine is required for voluntary movement, reward signaling, and attention control among other functions. The effects of dopamine on target cells have been extensively studied. By contrast, mechanisms that regulate the development and activity of dopamine neurons themselves are not well understood. Such mechanisms could be important targets for the treatment of neurological and psychiatric disorders that are associated with the dysfunction of brain dopamine systems. To identify novel genes that function in dopamine neurons, we studied the simple nervous system of the nematode Caenorhabditis elegans. C. elegans contains eight dopamine neurons that mediate stereotyped behaviors and are accessible to molecular, genetic and physiological analysis. We have sequenced the mRNAs of C. elegans dopamine neurons and identified genes whose transcripts are: (1) highly enriched in dopamine neurons compared to other neurons, (2) conserved with mammalian genes, and (3) produce a defect in dopamine-dependent modulation of locomotion upon mutating. This proposal focuses on a gene we have identified by this screen that encodes a leucine-rich repeat- containing (LRR) protein. LRR proteins play key roles in instructing axonal growth and synapse formation. In humans, mutations in LRR proteins are linked to several dopamine-related movement and neuropsychiatric disorders including Parkinson's disease, ADHD, and schizophrenia. However their precise roles in regulating cell development and function remain poorly understood. The proposed research will determine the function of an LRR protein in dopamine signaling, which will advance our understanding of the mechanisms required in vivo for dopamine signaling and of the roles that evolutionarily conserved LRR proteins play in the nervous system.

Public Health Relevance

Dopamine is a key neurochemical that is important for diverse neurophysiological processes, and many neurological and psychiatric disorders such as Parkinson's disease, schizophrenia, and ADHD are linked to defects in dopamine signaling in the brain. We have used a powerful genetic model to screen for molecules that are required for the function of dopamine neurons, and we have identified a member of a family of neuronal cell-surface proteins involved in neuronal development and circuit assembly. Studying the function of this member of a family of neuronal cell-surface proteins will help advance our understanding of the molecules required by dopamine neurons and inform the development of novel therapies for the treatment of neuropsychiatric diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Neurological Sciences Training Initial Review Group (NST)
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Sieber, Beth-Anne
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New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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