Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression

• Published in: Neuron (Cambridge, Mass.) Vol. 112; no. 9; pp. 1426 - 1443.e11
• Main Authors: Krontira, Anthi C., Cruceanu, Cristiana, Dony, Leander, Kyrousi, Christina, Link, Marie-Helen, Rek, Nils, Pöhlchen, Dorothee, Raimundo, Catarina, Penner-Goeke, Signe, Schowe, Alicia, Czamara, Darina, Lahti-Pulkkinen, Marius, Sammallahti, Sara, Wolford, Elina, Heinonen, Kati, Roeh, Simone, Sportelli, Vincenza, Wölfel, Barbara, Ködel, Maik, Sauer, Susann, Rex-Haffner, Monika, Räikkönen, Katri, Labeur, Marta, Cappello, Silvia, Binder, Elisabeth B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2024
• Subjects: Animals; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; cerebral organoids; developing mouse cortex; dexamethasone; Female; Gene Expression Regulation, Developmental - drug effects; glucocorticoids; Glucocorticoids - pharmacology; gyrified species; Humans; ITU cohort; Male; Medicin och hälsovetenskap; Mendelian randomization; Mice; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; neurogenesis; Neurogenesis - drug effects; Neurogenesis - physiology; Neurons - drug effects; Neurons - metabolism; Organoids - drug effects; Organoids - metabolism; Pregnancy; progenitors; Promyelocytic Leukemia Zinc Finger Protein - metabolism; ZBTB16; cerebral organoids; dexamethasone; progenitors; developing mouse cortex; ZBTB16; ITU cohort; gyrified species; neurogenesis; glucocorticoids; Mendelian randomization
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2024.02.005

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. [Display omitted] •Glucocorticoids increase PAX6+EOMES+ basal progenitors and upper-layer neurons•ZBTB16 is necessary and sufficient for the glucocorticoid effects on neurogenesis•ZBTB16 activates gyrified species-enriched processes in a lissencephalic cortex•Glucocorticoid excess during neurogenesis relates to beneficial postnatal outcomes Krontira et al. study the effects of glucocorticoids on neurogenesis in human cerebral organoids and mice. They find that glucocorticoids, via ZBTB16, increase PAX6+EOMES+ basal progenitors, a cell type enriched in species with a gyrified brain, and upper-layer neurons. This is associated with beneficial postnatal outcomes such as enhanced cognitive performance.