Mechanics of morphogenesis in neural development: In vivo, in vitro, and in silico

Morphogenesis in the central nervous system has received intensive attention as elucidating fundamental mechanisms of morphogenesis will shed light on the physiology and pathophysiology of the developing central nervous system. Morphogenesis of the central nervous system is of a vast topic that includes important morphogenetic events such as neurulation and cortical folding. Here we review three types of methods used to improve our understanding of morphogenesis of the central nervous system: in vivo experiments, organoids (in vivo), and computational models (in silico). The in vivo experiments are used to explore cellular- and tissue-level mechanics and interpret them on the roles of neurulation morphogenesis. Recent advances in human brain organoids have provided new opportunities to study morphogenesis and neurogenesis to compensate for the limitations of in vivo experiments, as organoid models are able to recapitulate some critical neural morphogenetic processes during early human brain development. Due to the complexity and costs of in vivo and in vitro studies, a variety of computational models have been developed and used to explain the formation and morphogenesis of brain structures. We review and discuss the advantages and disadvantages of these methods and their usage in the studies on morphogenesis of the central nervous system. Notably, none of these methods alone is sufficient to unveil the biophysical mechanisms of morphogenesis, thus calling for the interdisciplinary approaches using a combination of these methods in order to test hypotheses and generate new insights on both normal and abnormal development of the central nervous system.

Statement of Significance: The understanding of the central nervous system is essential to provide supports to treat and prevent neurological conditions. Mechanisms of morphogenesis therein can be elucidated from multiple unique perspectives via multidisciplinary approaches. The in vivo experiments, organoid models, and computational modeling are three most effective ways to study brain morphogenesis. In vivo experiments on live animals provide important evidence for studying the roles of mechanical forces in morphogenetic events. The human brain organoid models can greatly assist to study early human brain development and closely simulate the in-vivo counterpart. Moreover, computational models based on physical principles can test hypotheses in conjunctions with experiments to facilitate understanding of the spatial and temporal evolution of these complex structures. The combination of these approaches can complement each other to unveil fundamental mechanisms of the neural morphogenesis and shed light on the development, prevention, and treatment of neurological disorders.