FOXG1 dose tunes cell proliferation dynamics in human forebrain progenitor cells

• Published in: Stem cell reports Vol. 17; no. 3; pp. 475 - 488
• Main Authors: Hettige, Nuwan C., Peng, Huashan, Wu, Hanrong, Zhang, Xin, Yerko, Volodymyr, Zhang, Ying, Jefri, Malvin, Soubannier, Vincent, Maussion, Gilles, Alsuwaidi, Shaima, Ni, Anjie, Rocha, Cecilia, Krishnan, Jeyashree, McCarty, Vincent, Antonyan, Lilit, Schuppert, Andreas, Turecki, Gustavo, Fon, Edward A., Durcan, Thomas M., Ernst, Carl
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-03-2022; Elsevier
• Subjects: BF-1; Cell Proliferation; cilia; forebrain; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXG1; Humans; iPSC; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; neural progenitor cell; neurodevelopment; Prosencephalon - metabolism; Stem Cells - metabolism; Syndrome; neurodevelopment; cell proliferation; FOXG1; BF-1; iPSC; forebrain; cilia; neural progenitor cell
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2022.01.010

Heterozygous loss-of-function mutations in Forkhead box G1 (FOXG1), a uniquely brain-expressed gene, cause microcephaly, seizures, and severe intellectual disability, whereas increased FOXG1 expression is frequently observed in glioblastoma. To investigate the role of FOXG1 in forebrain cell proliferation, we modeled FOXG1 syndrome using cells from three clinically diagnosed cases with two sex-matched healthy parents and one unrelated sex-matched control. Cells with heterozygous FOXG1 loss showed significant reduction in cell proliferation, increased ratio of cells in G0/G1 stage of the cell cycle, and increased frequency of primary cilia. Engineered loss of FOXG1 recapitulated this effect, while isogenic repair of a patient mutation reverted output markers to wild type. An engineered inducible FOXG1 cell line derived from a FOXG1 syndrome case demonstrated that FOXG1 dose-dependently affects all cell proliferation outputs measured. These findings provide strong support for the critical importance of FOXG1 levels in controlling human brain cell growth in health and disease.
•FOXG1 syndrome neural progenitor cells show slower G1 phase exit and proliferation•FOXG1 syndrome neural progenitor cells have increased frequency of primary cilia•Engineered FOXG1 dose correlates with proliferation and frequency of primary cilia
Hettige and colleagues model dosage of FOXG1 in human neural progenitor cells. They show that differing levels of FOXG1 modify cell proliferation and frequency of primary cilia.