Human Brain Organoids to Decode Mechanisms of Microcephaly.

Elke Gabriel,Jay Gopalakrishnan,Nazlican Altinisik,Anand Ramani

doi:10.3389/fncel.2020.00115

Elke Gabriel, Jay Gopalakrishnan + Show 2 more

Open Access

https://doi.org/10.3389/fncel.2020.00115

Copy DOI

Abstract

Brain organoids are stem cell-based self-assembling 3D structures that recapitulate early events of human brain development. Recent improvements with patient-specific 3D brain organoids have begun to elucidate unprecedented details of the defective mechanisms that cause neurodevelopmental disorders of congenital and acquired microcephaly. In particular, brain organoids derived from primary microcephaly patients have uncovered mechanisms that deregulate neural stem cell proliferation, maintenance, and differentiation. Not only did brain organoids reveal unknown aspects of neurogenesis but also have illuminated surprising roles of cellular structures of centrosomes and primary cilia in regulating neurogenesis during brain development. Here, we discuss how brain organoids have started contributing to decoding the complexities of microcephaly, which are unlikely to be identified in the existing non-human models. Finally, we discuss the yet unresolved questions and challenges that can be addressed with the use of brain organoids as in vitro models of neurodevelopmental disorders.

Highlights

Our knowledge of the mechanisms of human brain development is limited mainly because the human brain is enormously complex in its cell diversity, composition, and architecture (Northcutt and Kaas, 1995; Borrell and Gotz, 2014)
Using patient-derived brain organoids, Gabriel et al showed that neural progenitor cells (NPCs) harboring a mutation in CPAP has retarded cilia disassembly exhibiting an extended G1-S transition
Unless and until cell death phenomena are prominently observed in a patient-derived organoid model, premature differentiation of NPCs leading to NPCs depletion makes most physiological sense as a mechanism causing microcephaly

Summary

Introduction

Our knowledge of the mechanisms of human brain development is limited mainly because the human brain is enormously complex in its cell diversity, composition, and architecture (Northcutt and Kaas, 1995; Borrell and Gotz, 2014). These studies have unequivocally identified a surprising mechanism that underlay the formation of small-sized brain organoids as a consequence of impaired proliferation and premature neuronal differentiation of neural progenitors (Lancaster and Knoblich, 2014; Gabriel et al, 2016).

Results

Conclusion