Neurodevelopment and Neurodevelopmental Disorder

the adolescence where differential expressions among area reappear [8]. The spatial part of transcriptome analysis gave the proof of structure gene regulation in human brain. Especially, differences in gene expression profiling were demonstrated between brain substructures or sites with the presence of region-specific genes [9–11]. Hawrylycz et al. combined histological analysis with microarray in 900 neuroanatomic subdivisions from two human brains and observed that the spatial topography of the neocortex is reflected in its transcriptomic topography where closer cortical regions have similar gene expression [12]. However, symmetry bilaterally between two hemispheres was observed during development [8, 9, 11]. In addition, the gene expression variability exists also between layers of neocortex. The neocortex consists of six horizontal layers with subsets of neurons, the transcriptional analysis of the layers in prefrontal cortex showed human specific layer gene expression patterns [13]. A study realized by Miller et al. demonstrated differential gene expression between proliferative and postmitotic layers in mid gestation human fetal brain with the presence of a molecular gradient frontotemporal in cortical layers [14]. These observations supported the gene expression gradients

Systems Biology Perspectives for Studying Neurodevelopmental Events

DOI: http://dx.doi.org/10.5772/intechopen.85072

While informative, the transcriptome analysis over the whole brain or performed on specific regions is issued from the analysis of multiple cells possibly presenting heterogeneous cell types populations. The development in single-cell transcriptomics appears as a relevant alternative for gathering information about cell types. The single-cell whole transcriptomic analysis permitted to identify cellular heterogeneity in the brain and subtypes of neuronal cells with differential gene expression between fetal and adult neurons [16]. Single nuclear transcriptome in the adult cerebral cortex was used to see diversity in neuronal subtypes and neuroanatomical areas [17]. Habib et al. combined this technique of single nucleus RNA-Seq with pulse-labeling proliferative cells using the thymidine analog, the


transcriptional trajectories single proliferating cells in the adult hippocampal neurogenic niche [18]. Similarly, a recent single-cell RNA-Seq study in the human fetal cortex and medial ganglionic eminence during prenatal neurogenesis demonstrated the presence of lineage specific trajectories dependent of transcription regulatory [19]. This study also demonstrated the modest transcriptional differences in cortical radial glia cascade which conducts robust typological differences in neurons. In the same context, Lake et al. combined single-cell sequencing with epigenome readouts in adult human brain cells to reveal chromatin/transcription factor regulatory events within distinct cell types [20]. Recently, Fan et al. also performed single-cell spatial transcriptome analysis in human brain mid gestation embryos, where they observed heterogeneity in each cortex region with no synchronization in cortex

The study of the transcriptional expression behavior during brain development is expected to enhance our understanding of pathological situations. Autism spectrum disorder (ASD), a heterogeneous pathology with prevalence of 1 in 59 children, is one of these examples. The pathogenesis of ASD is characterized by social impairments, disrupted communication skills and repetitive behaviors. Numerous genes were shown to be implicated in ASD and their gene co-expression and/or gene regulatory networks analyses are providing new insights on the impaired/ affected pathways on this disorder. In fact, several studies have tried to identify transcriptome alterations implicated in ASD using either DNA microarray hybridization assays or genome sequencing. By comparing autistic and control brain samples, upregulated genes implicated in immune function, while others repressed and

involved in neurodevelopment or synaptogenesis were highlighted [22–24].

Another study described a dysregulation in mitochondrial oxidative

along the anteroposterior axis of neocortex [15].

5-ethynyl-2<sup>0</sup>

137

development and maturation [21].

## Figure 1.

Timeline recapitulating major achievements in understanding of healthy or disease-affected human brain development by the use of functional genomics approaches.

integrative computational strategies in use. Importantly, the concept of gene networks as an approach to describe the inter-relationship among the various implicated genes on the disease is discussed and illustrated by the major efforts performed over the last years in the field of neurodevelopment and related diseases (Figure 1). Finally, we discuss the arrival of new technological approaches for enhancing our capacity to interrogate the human nervous tissue, which in contrary to other tissues, remained till recently restricted to postmortem collected samples.
