Cortical Organoids to Model Microcephaly

Abstract

How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man's place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies.

Keywords: Golgipathies; brain organoids; induced pluripotent stem cells (iPSCs); neocortex development; post-natal microcephaly; primary microcephaly.

Figure 1

Major cellular causes of primary microcephaly. Three major causes of primary microcephaly have been reported, leading to a reduced total number of cells at birth. Premature differentiation refers to an excessive early generation of neurons, leading to an exhaustion of the progenitor pool. This phenomenon can lead to a transient excess of neurons, but ultimately causes reduced neuronal production. Increased apoptotic cell death can occur in the newborn neurons or in the progenitor cells. In the former case, neuronal production is not affected, but eventually dies. In the latter case, neuronal production is directly affected. Reduced proliferation refers to an increased duration of the cell cycle, or to an exit from the cell cycle. This typically leads to a reduced mitotic index, which can be observed in apical or basal progenitors. A slower cell cycle directly reduces the number of neurogenic cell divisions. Interestingly, a slower cell cycle can also trigger premature neuronal differentiation, and therefore progenitor depletion.