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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Leblanc, Gabrielle G
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University of California San Francisco
Schools of Pharmacy
San Francisco
United States
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Berberoglu, Michael A; Dong, Zhiqiang; Li, Guangnan et al. (2014) Heterogeneously expressed fezf2 patterns gradient Notch activity in balancing the quiescence, proliferation, and differentiation of adult neural stem cells. J Neurosci 34:13911-23
Dong, Zhiqiang; Peng, Jisong; Guo, Su (2013) Stable gene silencing in zebrafish with spatiotemporally targetable RNA interference. Genetics 193:1065-71
Dong, Zhiqiang; Yang, Nan; Yeo, Sang-Yeob et al. (2012) Intralineage directional Notch signaling regulates self-renewal and differentiation of asymmetrically dividing radial glia. Neuron 74:65-78
Yang, Nan; Dong, Zhiqiang; Guo, Su (2012) Fezf2 regulates multilineage neuronal differentiation through activating basic helix-loop-helix and homeodomain genes in the zebrafish ventral forebrain. J Neurosci 32:10940-8
Ritter, Deborah I; Dong, Zhiqiang; Guo, Su et al. (2012) Transcriptional enhancers in protein-coding exons of vertebrate developmental genes. PLoS One 7:e35202
Chen, Lishan; Zheng, Jiashun; Yang, Nan et al. (2011) Genomic selection identifies vertebrate transcription factor Fezf2 binding sites and target genes. J Biol Chem 286:18641-9
Dong, Zhiqiang; Wagle, Mahendra; Guo, Su (2011) Time-lapse live imaging of clonally related neural progenitor cells in the developing zebrafish forebrain. J Vis Exp :
Mueller, Thomas; Dong, Zhiqiang; Berberoglu, Michael A et al. (2011) The dorsal pallium in zebrafish, Danio rerio (Cyprinidae, Teleostei). Brain Res 1381:95-105
Ritter, Deborah I; Li, Qiang; Kostka, Dennis et al. (2010) The importance of being cis: evolution of orthologous fish and mammalian enhancer activity. Mol Biol Evol 27:2322-32
Li, Qiang; Ritter, Deborah; Yang, Nan et al. (2010) A systematic approach to identify functional motifs within vertebrate developmental enhancers. Dev Biol 337:484-95

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