Acknowledgements

primate and human brains transcriptome analysis showed human specificity in gene expression profiling [82–84] with demonstration that genes differentially expressed are principally upregulated in human brains in contrast to other organs [85, 86]. In addition, the transcriptome remodeling during postnatal periods appears delayed in

More recently, the use of human-induced pluripotent stem cells (hIPSCs) com-

bined with in-vitro culture strategies for generating two- or three-dimensional nervous tissue appears as an alternative to animal model systems. In fact, nowadays

it is possible to generate hIPSCs from tissue samples collected from patients presenting neurological disorders which can be differentiated toward nervous tissue. In this context, a recent study compared the transcriptome of neural stem cells driven in-vitro toward corticogenesis and discovered a strong conservation with invivo gene expression with the conservation of cortical gene network implicated in ASD [73]. In contrast to the in-vitro neuronal differentiation in two dimensions, the generation of three-dimensional models (known as cerebral organoids) appears as a more relevant physiological model to study neurodevelopment [88–91]. Comparing human cerebral organoids and fetal brain development demonstrated the similarity in gene expression programs and epigenomic signatures [92–94]. Furthermore, single-cell transcriptome analysis over cerebral organoids revealed an important cellular heterogeneity, reminiscent to what is observed in the human brain [95]. As a consequence, the use of human cerebral organoids corresponds to a new approach for modeling the neuronal development and providing means to study neurogenesis from a systems biology perspective. For example, Mariani et al. generated cerebral organoids from hIPSCs derived from patients with ASD and recapitulated transcriptional programs present in fetal cortical development. In this study, the use of gene network analyses allowed to identify upregulated gene programs implicated in cell proliferation, neuronal differentiation and synaptic process [90]. Similarly, Amiri et al. identified gene modules implicated in ASD that overlap those described

previously in postmortem data. This study supported the idea that cerebral organoids provide means to reveal gene regulatory elements contributing to ASD [94]. Due to these success, major efforts focused on the development of protocols to generate tissues reminiscent to different brain structures like forebrain [90, 96], midbrain [96, 97], or hypothalamus [96] were developed. Recently, chimeric organoids issued from the fusion different regionalized organoids (like dorsalventral forebrain organoids) were generated to increase the complexity of the

The use of cerebral organoids as a model system for studying neurodevelopment and related diseases is in its infancy. This approach still requires improvements, for instance in the context of the reproducibility, but due to its alternative to human postmortem samples and animal models, it is expected to continue to evolve over the coming years. In fact, this tendency is also boosted by multiple other developments, including the use of CRISPR/CAS9 system to engineer organoids [99], the democratization of single cell omics strategies [95], as well as the gain in multidisciplinary approaches, specifically by the incorporation of computational approaches

Understanding the brain complexity corresponds to one of the major challenges for the scientific community. This does not only imply its physiological function, but also its relationship with the human mind. The use of omics strategies is revolutionizing the way to interpret any living system from the expression of their

generated tissues [98].

5. Conclusion

142

for modeling brain tissue organization [74].

human brain comparing to non-human primate [87].

Neurodevelopment and Neurodevelopmental Disorder

We thank all members of the SysFate lab for discussions related to the elaboration of this chapter. SysFate is supported by the "Genopole Thematic Incentive Actions" funding (referred to by their French acronym "ATIGE") and by the institutional bodies CEA, CNRS, and Université d'Evry, Université Paris-Saclay.
