A zinc-finger fusion protein refines Gal4-defined neural circuits

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A zinc-finger fusion protein refines Gal4-defined neural circuits
A zinc-finger fusion protein refines Gal4-defined neural circuits
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Molecular Brain
Publication Date:
20 August 2018
Raghu, S.V., Mohammad, F., Chua, J.Y. et al. A zinc-finger fusion protein refines Gal4-defined neural circuits. Mol Brain 11, 46 (2018). https://doi.org/10.1186/s13041-018-0390-7
The analysis of behavior requires that the underlying neuronal circuits are identified and genetically isolated. In several major model species—most notably Drosophila—neurogeneticists identify and isolate neural circuits with a binary heterologous expression-control system: Gal4–UASG. One limitation of Gal4–UASG is that expression patterns are often too broad to map circuits precisely. To help refine the range of Gal4 lines, we developed an intersectional genetic AND operator. Interoperable with Gal4, the new system’s key component is a fusion protein in which the DNA-binding domain of Gal4 has been replaced with a zinc finger domain with a different DNA-binding specificity. In combination with its cognate binding site (UASZ) the zinc-finger-replaced Gal4 (‘Zal1’) was functional as a standalone transcription factor. Zal1 transgenes also refined Gal4 expression ranges when combined with UASGZ, a hybrid upstream activation sequence. In this way, combining Gal4 and Zal1 drivers captured restricted cell sets compared with single drivers and improved genetic fidelity. This intersectional genetic AND operation presumably derives from the action of a heterodimeric transcription factor: Gal4-Zal1. Configurations of Zal1–UASZ and Zal1-Gal4-UASGZ are versatile tools for defining, refining, and manipulating targeted neural expression patterns with precision.
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Funding Info:
SVR, FM, JL, ML, SS and ACC received support from a Biomedical Research Council block grant to the Neuroscience Research Partnership and the Institute of Molecular and Cell Biology. CSB and ACC were supported by Biotechnology and Biological Sciences Research Council Project Grant BB/G024146/1. SVR, FM, and ACC also received support from Duke-NUS Medical School. CSB, FM, and ACC received support from a Wellcome Trust block grant to the University of Oxford. ACC received additional support from a Nuffield Department of Medicine Fellowship, A*STAR Joint Council Office grant 1231AFG030, NARSAD Young Investigator Award 17741, and Ministry of Education grants MOE2013-T2–2-054 and MOE2017-T2–1-089.
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