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

• DOI: 10.1016/j.neuron.2024.02.005
• Publication Date: 2024-03-04T15:32:31Z
• Authors: Anthi C. Krontira; Cristiana Cruceanu; Leander Dony; Christina Kyrousi; Marie-Helen Link; Nils Rek; Dorothee Pöhlchen; Catarina Raimundo; Signe Penner-Goeke; Alicia Schowe; Darina Czamara; Marius Lahti-Pulk...; Sara Sammallahti; Elina Wolford; Kati Heinonen; Simone Roeh; Vincenza Sportelli; Barbara Wölfel; Maik Ködel; Susann Sauer; Monika Rex-Haffner; Katri Räikkönen; Marta Labeur; Silvia Cappello; Elisabeth B. Binder
• Keywords: 3124; Cerebral Cortex; Neurons; Male; 570; Neurogenesis; 610; Gene Expression Regulation, Developmental; Organoids; Mice; Neural Stem Cells; 515; Pregnancy; Psychology; Humans; Animals; Female; Promyelocytic Leukemia Zinc Finger Protein; Glucocorticoids

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.