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.

The microcephaly geneASPMis required for the timely generation of human outer-radial glia progenitors by controlling mitotic spindle orientation

“…Several other centrosome-associated MCPH genes (CDK5RAP2, CPAP, STIL, WDR62) have been studied in animal models and human PSC-based neural models 58,63 . These studies reported diverse phenotypes including defects in neural stem cell mitosis, precocious differentiation, increased apoptosis, associated sometimes with mitotic spindle misorientation 45,[64][65][66][67] , but precocious generation of oRGC described here were not yet reported.…”

Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report

“…Seckel syndrome is a very rare and challenging neurological impairment that results in reduced brain dimensions and severe intellectual disability due to microcephaly, along with short stature [ 20 ]. Recently, multiple genetic studies have reported the probable role of RTTN variants in microcephaly syndromes [ 21 ]. RTTN expression pathways significantly control mitotic proliferation and modify spindle orientation in the cell-cycle [ 22 ].…”

Entosis implicates a new role for P53 in microcephaly pathogenesis, beyond apoptosis

“…Cortical organoids successfully model microcephaly by recapitulating early human brain development. [17,[134][135][136][137][138] Discovering entosis in human cortical organoids would support a role for entosis in human microcephaly patient pathology.…”