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

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-Pulkkinen; 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

doi:10.1016/j.neuron.2024.02.005

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

Neuron. 2024 Feb 27:S0896-6273(24)00089-8. doi: 10.1016/j.neuron.2024.02.005. Online ahead of print.

Authors

Anthi C Krontira¹, Cristiana Cruceanu², Leander Dony³, Christina Kyrousi⁴, Marie-Helen Link⁵, Nils Rek⁶, Dorothee Pöhlchen⁶, Catarina Raimundo⁵, Signe Penner-Goeke⁵, Alicia Schowe⁷, Darina Czamara⁵, Marius Lahti-Pulkkinen⁸, Sara Sammallahti⁹, Elina Wolford¹⁰, Kati Heinonen¹¹, Simone Roeh⁵, Vincenza Sportelli⁵, Barbara Wölfel⁵, Maik Ködel⁵, Susann Sauer⁵, Monika Rex-Haffner⁵, Katri Räikkönen¹⁰, Marta Labeur⁵, Silvia Cappello¹², Elisabeth B Binder¹³

Affiliations

¹ Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany; International Max Planck Research School for Translational Psychiatry, Munich 80804, Germany. Electronic address: anthi.krontira@bmc.med.lmu.de.
² Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
³ Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany; International Max Planck Research School for Translational Psychiatry, Munich 80804, Germany; Department for Computational Health, Helmholtz Munich, Neuherberg 85764, Germany; TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising 85354, Germany.
⁴ Developmental Neurobiology, Max Planck Institute of Psychiatry, Munich 80804, Germany; First Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, Athens 15784, Greece; University Mental Health, Neurosciences and Precision Medicine Research Institute "Costas Stefanis", Athens 15601, Greece.
⁵ Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany.
⁶ Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany; International Max Planck Research School for Translational Psychiatry, Munich 80804, Germany.
⁷ Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University, Munich 82152, Germany.
⁸ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland; Finnish Institute for Health and Welfare, Helsinki 00271, Finland; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
⁹ Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki 00014, Finland.
¹⁰ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
¹¹ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland; Psychology/Welfare, Faculty of Social Sciences, University of Tampere, Tampere 33014, Finland; Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON M5T 1P8, Canada.
¹² Developmental Neurobiology, Max Planck Institute of Psychiatry, Munich 80804, Germany; Physiological Genomics, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University (LMU), Munich 82152, Germany.
¹³ Department Genes and Environment, Max Planck Institute of Psychiatry, Munich 80804, Germany. Electronic address: binder@psych.mpg.de.

PMID: 38442714
DOI: 10.1016/j.neuron.2024.02.005

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.

Keywords: ITU cohort; Mendelian randomization; ZBTB16; cerebral organoids; developing mouse cortex; dexamethasone; glucocorticoids; gyrified species; neurogenesis; progenitors.