Senior Investigator
Ajay
Chitnis,
M.B.B.S., Ph.D.
Laboratory of Molecular Genetics
Dr. Chitnis received his M.B.B.S. from the University of Bombay, India, in 1984. He received his Ph.D. from the University of Michigan, Ann Arbor in 1991, where with John Kuwada he examined how early neurons establish brain tracts in the zebrafish embryo. Dr. Chitnis did postdoctoral training with Chris Kintner at the Salk Institute, where he studied the role of Notch signaling in selecting cells that become early neurons in the Xenopus neural plate, and then with Wolfgang Driever at Massachusetts General Hospital, where he identified zebrafish mutants with an aberrant pattern of early neurons. In 1997, Dr. Chitnis joined the Laboratory of Molecular Genetics in NICHD as an Investigator. His group uses a combination of cellular, molecular, genetic and computational approaches to understand how a relatively simple pattern of early neurons is established in the zebrafish neural plate.
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Each organ in our body represents a vast community of cells with distinct fate and morphology. The broad goal of the Section on Neural Developmental Dynamics is to understand how interactions between cells ensure that different types of cells differentiate in the correct number and location in a developing nervous system. They also investigate how, as cells begin to differentiate, progenitor populations are maintained to ensure the growth and development of the developing brain. They use a combination of cellular, molecular, genetic and computational approaches to understand the process of self-organization of the zebrafish nervous system during early development.
The research primarily examines the role of the Notch signaling pathway in determining cell diversity, in maintaining progenitors, and in determining the morphology of cells as they acquire distinct fates during neural development. Work in this area began with the analysis of zebrafish mutants with aberrant patterns of early neurogenesis. One of these mutants, mind bomb (mib), was found to encode a RING ubiquitin ligase responsible for promoting endocytosis of Delta. Having shown that Mib-mediated endocytosis of Delta is essential for effective Notch activation in a neighboring cell studies are now directed at understanding how the cell biology of Delta and Notch trafficking contributes to Notch signaling. The identification of additional Mib interacting proteins has led to studies directed at understanding the role of Mib in diverse cellular biological mechanisms including organization of cell polarity and morphogenesis in the nervous system. Finally, computational models are developed to understand the dynamic function of Notch signaling and to visualize how interactions between cells regulate neurogenesis in the developing brain.
Specific Goals:
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Understand the function of Mind bomb and the cell biology of Delta-Notch signaling
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Functional analysis of Mib interacting proteins
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Define mechanisms that establish and maintain neuronal progenitors
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Explore potential morphogenetic functions of Delta, Notch and Mib
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Develop computational models of genetic networks involving Notch signaling
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Early neurons in the zebrafish neural plate
Our goal is to understand how neurons are made in the correct number and location in the developing nervous system. To explore this problem we have been studying neurogenesis in the zebrafish embryo where neurons are distributed in a relatively simple pattern. In the caudal neural plate, which eventually forms the spinal cord, early neurons are distributed in three longitudinal domains where they form sensory neurons, interneurons and motor neurons, respectively. Expression of a basic helix-loop helix transcription factor, neurogenin1 (ngn1), gives cells the in these longitudinal domains the potential to become neurons. Within each "proneuronal" domain lateral inhibition, mediated by Notch signaling, limits the number of cells that are permitted to become neurons (Chitnis et al 1995). These observations underscore remarkable similarities in the mechanisms that operate during early neurogenesis in the Drosophila and vertebrate nervous systems.
We are using a combination of cellular, molecular and genetic approaches to understand the nature of neural precursors in the zebrafish neural plate and the function of proneural and neurogenic genes in their formation. We are also investigating mechanisms that determine expression of these genes in the neuroectoderm. To address some of these issues we have identified zebrafish mutants with an aberrant pattern of early neurons. Analysis of some of these mutants has revealed a gene that is essential for formation of early sensory neurons (Artinger et al, 1999), a role for Wnt signaling in patterning the anterior neuroectoderm (Kim et al 2000) and a novel gene in the Notch signaling pathway (in preparation). We are also using transgenic zebrafish with fluorescent neurons to continue our investigation of early neurogenesis (Park et al 2000) and have examined the mechanisms that determine hair cell fate in the migrating lateral line primordium (Itoh and Chitnis 2001).
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1) Itoh M, Chitnis AB (2001)
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Expression of proneural and neurogenic genes in the zebrafish lateral line primordium correlates with selection of hair cell fate in neuromasts.
- Mech Dev, 102, 263-6
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2) Kim, C-H, Oda T, Itoh M, Jiang D, Artinger KB, Chandrasekharappa SC, Driever W, Chitnis AB (2000)
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Repressor activity of Headless/Tcf3 is essential for vertebrate head formation.
- Nature , 407, 913-6
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3) Park HC, Kim CH, Bae YK, Yeo SY, Kim SH, Hong SK, Shin J, Yoo KW, Hibi M, Hirano T, Miki N, Chitnis AB, Huh TL (2000)
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Analysis of upstream elements in the HuC promoter leads to the establishment of transgenic zebrafish with fluorescent neurons.
- Developmental Biology, 227, 279-93
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4) Artinger, K.B., Chitnis, A.B., Mercola, M. & Driever W (1999)
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Zebrafish narrowminded suggests a genetic link between formation of neural crest and primary sensory neurons.
- Development, 126, 3969-3979
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5) Chitnis A, Henrique D, Lewis J, Ish-Horowicz D, and Kintner C (1995)
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Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta.
- Nature, 375, 761-766
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