Researchers in the Jane and Terry Semel Institute for Neuroscience and Human Behaviors at UCLA have developed four novel reporter mouse lines that illuminate morphologies of genetically-defined neurons and glia and can serve as novel platform for testing candidate therapeutics for neurodevelopmental, psychiatric and age-related brain diseases. The tools can also be used to test toxicities of any molecules to genetically-defined brain cells in vivo.
BACKGROUND:
Despite significant advances in understanding neuronal function, many barriers remain in elucidating brain organization and function. The limitations of current technologies to study the complex mammalian brain is one of the major impediments in developing the understanding and providing solutions to brain diseases. Existing methods, such as Golgi staining or in vitro dye filling, have many limitations including labor intensive procedures with poor scalability, difficulty to control labeling frequency, partial morphology of a labeled neuron within a brain slice, and incompatibility with modern molecular and genetic tools. The ability to evaluate the full morphology of individual neurons brain-wide and to do so at a simple, reproducible, and scalable manner will offer a functional and robust tool with which to study and diagnose brain morphology, function and disease.
INNOVATION:
Dr. Yang and colleagues at UCLA have developed four novel MORF (mononucleotide repeat frameshift) reporter mouse lines that allow the visualization of genetically-defined neurons. The MORF mouse lines allow Cre-dependent, sparse, and stochastic cell labeling and enable the visualization of full neuronal morphology from dendrites to axons and spines. One mice reporter has showcased the broadest utility in terms of non-toxic labeling of any Cre-defined cell types, its compatibility for 3D imaging in iDISCO+ cleared thick brain sections, and immune-electron microscopy (EM). The MORF technology will provide unprecedented throughput and resolution to reveal how genetically-defined neurons may alter their morphology in the context of normal brain function or brain diseases. This platform creates new opportunities for the systematic investigation of in vivo brain cell biology and can be used to test the toxicity and mode-of-action of any candidate therapeutics for brain diseases.
APPLICATIONS:
• Neurobiology research tool
• Visualizing detailed brain cell morphological phenotypes
• Testing therapeutics in mouse models of neurodevelopmental, neurodegenerative, psychiatric, age-related brain diseases
• Largescale mapping of genetically-defined morphologically-complex cell types in the brain and peripheral tissues
ADVANTAGES:
• Visualization of detailed morphology of genetically-defined cell types or a combination of such cell types in the brain and peripheral tissues
• Superior resolution of full morphologies of genetically-defined neurons and glial cells
• Simultaneous visualization of neuron morphology and biomolecules in normal or diseased brains
• Non-toxic labeling throughout lifespan of an animal from embryo to adult and aging process
• Compatible with 3D imaging in iDISCO+ and immune-EM
STATE OF DEVELOPMENT:
The study has shown these novel mouse lines can be used to cross with a Huntington's disease (HD) mouse model and to simultaneously reveal both the morphology of vulnerable neurons in HD, and the pathognomonic protein aggregates.
RELATED PAPERS:
Veldman, MB., et al. Brainwide Genetic Sparse Cell Labeling to Illuminate the Morphology of Neurons and Glia with Cre-dependent MORF Mice. Neuron (2020), https://doi.org/10.1016/j.neuron.2020.07.019