The Use of Stem Cell-Derived Neurons for Understanding Development and Disease of the Cerebellum

The cerebellum is a fascinating brain structure, containing more neurons than the rest of the brain combined. The cerebellum develops according to a highly orchestrated program into a well-organized laminar structure. Much has been learned about the underlying genetic networks controlling cerebellar development through the study of various animal models. Cerebellar development in humans however, is significantly protracted and more complex. Given that the cerebellum regulates a number of motor and non-motor functions and is affected in a wide variety of neurodevelopmental and neurodegenerative disorders, a better understanding of human cerebellar development is highly desirable. Pluripotent stem cells offer an exciting new tool to unravel human cerebellar development and disease by providing a dynamic and malleable platform, which is amenable to genetic manipulation and temporally unrestricted sampling. It remains to be seen, however, whether in vitro neuronal cultures derived from pluripotent stem cells fully recapitulate the formation and organization of the developing nervous system, with many reports detailing the functionally immature nature of these cultures. Nevertheless, recent advances in differentiation protocols, cell-sampling methodologies, and access to informatics resources mean that the field is poised for remarkable discoveries. In this review, we provide a general overview of the field of neuronal differentiation, focusing on the cerebellum and highlighting conceptual advances in understanding neuronal maturity, including a discussion of both current and emerging methods to classify, and influence neuroanatomical identity and maturation status.