The cerebellum coordinates and synchronizes balance, movement, emotion and cognition. Cerebellar defects contribute to disorders in motor control, equilibrium, posture and learning and are frequent pathological signs in epilepsy and autism. The seeming simplicity of cerebellar structure belies its developmental complexity, with reciprocal interactions between the two principal cell types, the Purkinje cells and granule cells. The resulting cell non-autonomous effects have been an obstacle to understanding the developmental mechanisms. The textbook view has been that Purkinje cells migrate by locomotion along radial glia fibers, and absence of an environmental cue, Reelin, inhibits detachment from the radial glia. However, there are reasons to question this view. First, Purkinje cells were recently seen to move across rather than along radial glia. Second, even though Reelin regulates neuron migrations in the forebrain, it regulates glia-independent migration. In addition, we recently found that an E3 ubiquitin ligase, CRL5, regulates Purkinje cell migration, but, again, the cellular mechanism is unknown. These issues are currently difficult to address because it is challenging to genetically manipulate individual Purkinje cells and observe their migrations in a normal environment. Therefore, our immediate goal is to adapt methods to track and genetically alter Purkinje cells as they migrate and differentiate in the cerebellum. Then, we will combine these new methods with our experience studying neuron migration in the neocortex in order to address key questions of how Purkinje cells migrate and how they are regulated by Reelin and CRL5. An ancillary benefit of the proposed research is that the methods we develop will be invaluable for future investigation of pre- and post-natal cerebellar development, disease and degeneration.

Public Health Relevance

The cerebellum is a small part of the brain yet contains most of the neurons. It is best known to regulate balance and movement, but is also implicated in emotion and thought. Anatomically, the cerebellum is one of the simplest of brain regions, with two main types of neurons connected by stereotyped circuits. The development of this simple structure is complex, however, with neurons migrating into the cerebellum from different directions. We propose to develop and apply novel methods to understand how one cell type, the Purkinje cell, migrates to its proper place in the developing cerebellum. The methods we develop should be useful to other researchers to investigate cerebellar abnormalities and degeneration.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Fred Hutchinson Cancer Research Center
United States
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Wang, Liang; Cooper, Jonathan A (2017) Optogenetic control of the Dab1 signaling pathway. Sci Rep 7:43760
Cooper, Jonathan A (2014) Molecules and mechanisms that regulate multipolar migration in the intermediate zone. Front Cell Neurosci 8:386