Abstract
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.
Highlights
The development of the nervous system is guided by temporally programmed, spatially distinct morphogen gradients
In vitro reproduction of these cues can be achieved in pluripotent stem cells (PSCs), facilitating cellular differentiation into distinct neuronal and glial subtypes (Zhang et al, 2001; Wichterle et al, 2002)
Whilst surviving transplantation, purified Kirrel2-positive cells could not be maintained alone in vitro, but required co-culture with RLderived granule cells (GCs) for their further differentiation, and maturation. This is consistent with other studies reporting a drastic improvement in embryonic stem cells (ESCs)-derived Purkinje cells (PCs) generation through co-culture with dissociated cerebellar cultures or organotypic slice cultures of whole mouse cerebellum (Tao et al, 2010), and highlights the need for an appropriate trophic environment for the in vitro culture of neuronal subpopulations
Summary
The development of the nervous system is guided by temporally programmed, spatially distinct morphogen gradients. Current challenges include the development of standardized, robust protocols for differentiation, as well as classification strategies that can effectively relate in vitro-derived cell types to their in vivo counterparts, including assessing their state of maturity. Methodologies to generate cerebellar neurons from human PSCs and to model cerebellar disorders are beginning to emerge (Muguruma et al, 2015; Ishida et al, 2016; Sundberg et al, 2018; Watson et al, 2018).
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