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  3. Brainwide Genetic Sparse Cell Labeling to Illuminate the Morphology of Neurons and Glia with Cre-Dependent MORF Mice

Brainwide Genetic Sparse Cell Labeling to Illuminate the Morphology of Neurons and Glia with Cre-Dependent MORF Mice

  • Neuron. 2020 Oct 14;108(1):111-127.e6. doi: 10.1016/j.neuron.2020.07.019.
Matthew B Veldman 1,  Chang Sin Park 1,  Charles M Eyermann 1,  Jason Y Zhang 1,  Elizabeth Zuniga-Sanchez 2,  Arlene A Hirano 3,  Tanya L Daigle 4,  Nicholas N Foster 5,  Muye Zhu 5,  Peter Langfelder 1,  Ivan A Lopez 6,  Nicholas C Brecha 7,  S Lawrence Zipursky 2,  Hongkui Zeng 4,  Hong-Wei Dong 8,  X William Yang 9
Affiliations

Affiliations

  • 1 Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, and Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 3 Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Veterans Administration of Greater Los Angeles Health System, Los Angeles, CA 90073, USA.
  • 4 Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • 5 Center for Integrative Connectomics, University of Southern California Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, USC, Los Angeles, CA, 90033, USA.
  • 6 Cellular and Molecular Biology of the Inner Ear Laboratory, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 7 Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Veterans Administration of Greater Los Angeles Health System, Los Angeles, CA 90073, USA; Departments of Medicine and Ophthalmology, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 8 Center for Integrative Connectomics, University of Southern California Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, USC, Los Angeles, CA, 90033, USA; Zilkha Neurogenetic Institute, and Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • 9 Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, and Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: xwyang@mednet.ucla.edu.
PMID: 32795398 DOI: 10.1016/j.neuron.2020.07.019
Abstract

Cajal recognized that the elaborate shape of neurons is fundamental to their function in the brain. However, there are no simple and generalizable genetic methods to study neuronal or glial cell morphology in the mammalian brain. Here, we describe four mouse lines conferring Cre-dependent sparse cell labeling based on mononucleotide repeat frameshift (MORF) as a stochastic translational switch. Notably, the optimized MORF3 mice, with a membrane-bound multivalent immunoreporter, confer Cre-dependent sparse and bright labeling of thousands of neurons, astrocytes, or microglia in each brain, revealing their intricate morphologies. MORF3 mice are compatible with imaging in tissue-cleared thick brain sections and with immuno-EM. An analysis of 151 MORF3-labeled developing retinal horizontal cells reveals novel morphological cell clusters and axonal maturation patterns. Our study demonstrates a conceptually novel, simple, generalizable, and scalable mouse genetic solution to sparsely label and illuminate the morphology of genetically defined neurons and glia in the mammalian brain.

Keywords

Cre; MORF; astrocyte; imaging; microglia; morphology; neuron; reconstruction; spaghetti monster; sparse labeling.

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