Abstract
Neural epidermal growth factor-like like 2 (NELL2) is a cytoplasmic and secreted glycosylated protein with six epidermal growth factor-like domains. In animal models, NELL2 is predominantly expressed in neural tissues where it regulates neuronal differentiation, polarization, and axon guidance, but little is known about the role of NELL2 in human brain development. In this study, we show that rostral neural stem cells (rNSC) derived from human-induced pluripotent stem cell (hiPSC) exhibit particularly strong NELL2 expression and that NELL2 protein is enriched at the apical side of neural rosettes in hiPSC-derived brain organoids. Following differentiation of human rostral NSC into neurons, NELL2 remains robustly expressed but changes its subcellular localization from >20 small cytoplasmic foci in NSC to one–five large peri-nuclear puncta per neuron. Unexpectedly, we discovered that in human brain organoids, NELL2 is readily detectable in the oligodendroglia and that the number of NELL2 puncta increases as oligodendrocytes mature. Artificial intelligence-based machine learning further predicts a strong association of NELL2 with multiple human white matter diseases, suggesting that NELL2 may possess yet unexplored roles in regulating oligodendrogenesis and/or myelination during human cortical development and maturation.
Highlights
The neural tube is the precursor of the brain and spinal cord and is derived from embryonic neural stem cells (NSCs) (Pai et al, 2012)
Our gene expression and network analysis revealed that Nell2 is one of the 10 hub genes with the potential to regulate the function of rostral neural stem cells (rNSC) during embryonic development and identified Nell2 as a standout gene that is expressed in rNSC derived from mouse embryos and mES cells
We demonstrate that 30% of mouse rostral hub genes are expressed in human rNSCs, namely, GRM3, CTNND2, and Neural epidermal growth factor-like like 2 (NELL2)
Summary
The neural tube is the precursor of the brain and spinal cord and is derived from embryonic neural stem cells (NSCs) (Pai et al, 2012). During early central nervous system (CNS) development, rostral and caudal NSCs are derived from distinct lineages, namely, neuroectoderm (NEct) and neuromesodermal progenitors (NMPs), respectively R. et al, 2021; Shaker et al, 2021c; Hudson and Yasuo, 2021) These two distinct populations differ in proliferation rates, differentiation potential, and ECM adhesion NSCs can be found across the brain and spinal neural tube during development and are maintained to adulthood to meet the demand of adult neurogenesis and gliogenesis (Sabelström et al, 2014; Kim et al, 2015; Rusznák et al, 2016).
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