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specialized neural progenitors responsible for generating astrocytes and oligodendrocytes, respectively. 29,30 These
both neuronal and glial cells. 22 glial cells integrate into neuronal circuits, supporting

RGCs exhibit a highly polarized morphology with synaptic function and maintenance.
an apically positioned soma and elongated radial NDDs encompass a broad spectrum of conditions
processes extending to the pial surface. Initially, they characterized by abnormal brain development, leading
divide symmetrically to amplify the progenitor pool. As to cognitive, emotional, and behavioral impairments.
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corticogenesis proceeds, RGCs transition to asymmetric Affecting approximately 5% of children worldwide, NDDs
divisions, producing neurons and additional RGCs in manifest with diverse clinical features, including intellectual
a process termed direct neurogenesis. 23,24 Alternatively, disability, autism spectrum disorder, and developmental
asymmetric divisions generate intermediate progenitor delays. Their etiology is multifactorial, involving intricate
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cells in the subventricular zone (SVZ), which undergo genetic and environmental interactions. Animal models,
limited proliferation before giving rise to neurons through particularly transgenic rodents, have been instrumental in
indirect neurogenesis. Another distinct progenitor uncovering the molecular mechanisms underlying NDDs
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population, oRGCs, emerges in the outer SVZ. Unlike and in testing pharmacological interventions (Figure 1).
RGCs, oRGCs lack apical membrane attachment but retain However, their inherent limitations, including structural
radial processes extending to the pial surface. They exhibit and functional differences from the human brain and
enhanced proliferative capacity, becoming the predominant limited genetic heterogeneity, often hinder translational
progenitor type in the human brain around mid-gestation success, underscoring the need to develop alternative
and substantially contributing to cortical neurogenesis. 26 models. 33,34
Neuronal differentiation and migration occur hPSCs provide a powerful platform for investigating
concurrently, ensuring proper integration into developing human brain development and NDD pathology. These
networks. 27 Dendritic spine morphogenesis and cells, which include embryonic stem cells (ESCs) and
synaptogenesis establish synaptic connectivity, followed induced pluripotent stem cells (iPSCs), exhibit remarkable
by synaptic pruning, which refines neuronal circuits self-renewal and differentiation capabilities. 35-37 iPSCs,
throughout development and into adulthood. Around generated by reprogramming somatic cells through
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mid-gestation, RGCs and oRGCs shift from neurogenesis transcription factors such as Oct4, Klf4, Sox2, and c-Myc,
to gliogenesis, giving rise to astrocyte progenitor cells and enable the study of patient-specific disease mechanisms and
oligodendrocyte progenitor cells, which differentiate into facilitate drug screening and gene therapy development. 38,39

Figure 1. Comparative experimental models for human brain development and neurodevelopmental disorders

Volume 1 Issue 3 (2025) 3 doi: 10.36922/OR025100010