The Interleukin 3 Gene (IL3) Contributes to Human Brain Volume Variation by Regulating Proliferation and Survival of Neural Progenitors

AbstractIn this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate, downregulation of genes involved in oxidative phosphorylation (OXPHOS), and an upregulation of glycolytic capacity was apparent upon loss of p53. In addition, p53KD neural stem cells display an increased pace of differentiating into neurons and exhibit a phenotype corresponding to more mature neurons compared to control neurons. Using brain organoids, we modeled more specifically cortical neurogenesis. Here we found that p53 loss resulted in brain organoids with disorganized stem cell layer and reduced cortical progenitor cells and neurons. Similar to NES cells, neural progenitors isolated from brain organoids also show a downregulation in several OXPHOS genes. Taken together, this demonstrates an important role for p53 in controlling genomic stability of neural stem cells and regulation of neuronal differentiation, as well as maintaining structural organization and proper metabolic gene profile of neural progenitors in human brain organoids.

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Faculty Opinions recommendation of Recent zika virus isolates induce premature differentiation of neural progenitors in human brain organoids.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727250872.793560538 ◽

2019 ◽

Author(s):

Alysson Muotri

Keyword(s):

Human Brain ◽

Zika Virus ◽

Neural Progenitors ◽

Virus Isolates

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Human Brain Volume: What’s in the Genes#

Handbook of Behavior Genetics ◽

10.1007/978-0-387-76727-7_10 ◽

2009 ◽

pp. 137-157 ◽

Cited By ~ 1

Author(s):

Jiska S. Peper ◽

Marcel P. Zwiers ◽

Dorret I. Boomsma ◽

Reneacute S. Kahn ◽

Hilleke E. Hulshoff Pol

Keyword(s):

Human Brain ◽

Brain Volume

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The Development of Human Brain Volume in the Biological Evolution

Modern Anthropology ◽

10.12677/ma.2015.33005 ◽

2015 ◽

Vol 03 (03) ◽

pp. 32-42

Author(s):

树华姜

Keyword(s):

Human Brain ◽

Brain Volume ◽

Biological Evolution

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Normative human brain volume growth

Journal of Neurosurgery Pediatrics ◽

10.3171/2017.10.peds17141 ◽

2018 ◽

Vol 21 (5) ◽

pp. 478-485 ◽

Cited By ~ 4

Author(s):

Mallory Peterson ◽

Benjamin C. Warf ◽

Steven J. Schiff

Keyword(s):

Human Brain ◽

Power Law ◽

Goodness Of Fit ◽

Brain Volume ◽

Volume Growth ◽

Growth Charts ◽

Brain Growth ◽

Statistical Measures ◽

Curve Fit ◽

Males And Females

OBJECTIVEWhile there is a long history of interest in measuring brain growth, as of yet there is no definitive model for normative human brain volume growth. The goal of this study was to analyze a variety of candidate models for such growth and select the model that provides the most statistically applicable fit. The authors sought to optimize clinically applicable growth charts that would facilitate improved treatment and predictive management for conditions such as hydrocephalus.METHODSThe Weibull, two-term power law, West ontogenic, and Gompertz models were chosen as potential models. Normative brain volume data were compiled from the NIH MRI repository, and the data were fit using a nonlinear least squares regression algorithm. Appropriate statistical measures were analyzed for each model, and the best model was characterized with prediction bound curves to provide percentile estimates for clinical use.RESULTSEach model curve fit and the corresponding statistics were presented and analyzed. The Weibull fit had the best statistical results for both males and females, while the two-term power law generated the worst scores. The statistical measures and goodness of fit parameters for each model were provided to assure reproducibility.CONCLUSIONSThe authors identified the Weibull model as the most effective growth curve fit for both males and females. Clinically usable growth charts were developed and provided to facilitate further clinical study of brain volume growth in conditions such as hydrocephalus. The authors note that the homogenous population from which the normative MRI data were compiled limits the study. Gaining a better understanding of the dynamics that underlie childhood brain growth would yield more predictive growth curves and improved neurosurgical management of hydrocephalus.

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