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The Journal of Neuroscience, August 23, 2006, 26(34):8734-8747; doi:10.1523/JNEUROSCI.2106-06.2006

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Development/Plasticity/Repair
Phenotypes of Drosophila Brain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory

Robert Kraft,¹ Mindy M. Escobar,¹ Martha L. Narro,¹ Jackie L. Kurtis,¹ Alon Efrat,² Kobus Barnard,^2,3 and Linda L. Restifo^1,3,4

¹Arizona Research Laboratories Division of Neurobiology, ²Department of Computer Science, and ³Interdisciplinary Program in Cognitive Science, University of Arizona, Tucson, Arizona 85721, and ⁴Department of Neurology, Arizona Health Sciences Center, Tucson, Arizona 85724

Correspondence should be addressed to Linda L. Restifo, University of Arizona, 1040 East 4th Street, Tucson, AZ 85721-0077 Email: LLR{at}neurobio.arizona.edu

Subtle cellular phenotypes in the CNS may evade detection by routine histopathology. Here, we demonstrate the value of primary culture for revealing genetically determined neuronal phenotypes at high resolution. Gamma neurons of Drosophila melanogaster mushroom bodies (MBs) are remodeled during metamorphosis under the control of the steroid hormone 20-hydroxyecdysone (20E). In vitro, wild-type neurons retain characteristic morphogenetic features, notably a single axon-like dominant primary process and an arbor of short dendrite-like processes, as determined with microtubule-polarity markers. We found three distinct genetically determined phenotypes of cultured neurons from grossly normal brains, suggesting that subtle in vivo attributes are unmasked and amplified in vitro. First, the neurite outgrowth response to 20E is sexually dimorphic, being much greater in female than in male neurons. Second, the neuron-specific "naked runt" phenotype results from transgenic insertion of an MB-specific promoter. Third, the recessive, pan-neuronal "filagree" phenotype maps to singed, which encodes the actin-bundling protein fascin. Fascin deficiency does not impair the 20E response, but neurites fail to maintain their normal, nearly straight trajectory, instead forming curls and hooks. This is accompanied by abnormally distributed filamentous actin. This is the first demonstration of fascin function in neuronal morphogenesis. Our findings, along with the regulation of human Fascin1 (OMIM 602689 [OMIM] ) by CREB (cAMP response element-binding protein) binding protein, suggest FSCN1 as a candidate gene for developmental brain disorders. We developed an automated method of computing neurite curvature and classifying neurons based on curvature phenotype. This will facilitate detection of genetic and pharmacological modifiers of neuronal defects resulting from fascin deficiency.

Key words: mushroom body; neurogenetics; actin; ecdysone; software; neurite curvature; sexual dimorphism; plasticity; cytoskeleton

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Received May 17, 2006; revised July 14, 2006; accepted July 16, 2006.

Correspondence should be addressed to Linda L. Restifo, University of Arizona, 1040 East 4th Street, Tucson, AZ 85721-0077 Email: LLR{at}neurobio.arizona.edu

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