Dopaminergic (DA) neurons synthesize and release neurotransmitters dopamine. The importance of DA neurons is underscored by their involvement in multiple human neurological disorders, for instance, Parkinson's disease. Despite their functional significance, the mechanisms determining the development of these neurons are not well understood. Elucidation of these mechanisms is essential to defining and interpreting the causes of disorders affecting DA neurons and developing regenerative therapy for treating Parkinson's disease. Meanwhile, understanding the development of DA neurons will also shed light on fundamental mechanisms governing cell identity and diversity and neural circuit formation in the vertebrate nervous system. The long-term goal of this project is to understand the molecular mechanisms that control the identity and connectivity of subtypes of DA neurons in vertebrates. We are taking a genetic approach in zebrafish, a vertebrate model organism that offers a unique combination of excellent genetics and embryology. We have localized major DA neuronal subtypes in developing zebrafish. By carrying out a genetic screen based on immunohistochemistry, we have identified mutations in three genes that are required for proper development of subtypes of DA neurons. Molecular cloning of the foggy gene revealed the importance of regulated transcription elongation in DA neuron development. Thus, we shall explore how this previously under-appreciated mode of gene regulation is involved in DA neuron development. Phenotypic analysis suggested that the motionless and twin-of-motionless mutations disrupt a signal important for DA neuron induction. Therefore, their molecular identity will be determined. By analysis of cloned genes and existing mutations, we will identify essential machinery involved in controlling DA neuron development. These molecules will not only provide important insights into vertebrate neural development, but may also help develop regenerative therapy for treating neurological disorders such as Parkinson's disease.
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