1. Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression.
- Author
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Krontira AC, Cruceanu C, Dony L, Kyrousi C, Link MH, Rek N, Pöhlchen D, Raimundo C, Penner-Goeke S, Schowe A, Czamara D, Lahti-Pulkkinen M, Sammallahti S, Wolford E, Heinonen K, Roeh S, Sportelli V, Wölfel B, Ködel M, Sauer S, Rex-Haffner M, Räikkönen K, Labeur M, Cappello S, and Binder EB
- Subjects
- Humans, Animals, Mice, Female, Pregnancy, Neurons metabolism, Neurons drug effects, Organoids drug effects, Organoids metabolism, Gene Expression Regulation, Developmental drug effects, Neural Stem Cells drug effects, Neural Stem Cells metabolism, Male, Neurogenesis drug effects, Neurogenesis physiology, Glucocorticoids pharmacology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cerebral Cortex cytology, Promyelocytic Leukemia Zinc Finger Protein metabolism
- Abstract
Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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