FOXG1 dose tunes cell proliferation dynamics in human forebrain progenitor cells

• DOI: 10.1016/j.stemcr.2022.01.010
• Publication Date: 2022-02-10T15:38:58Z
• Authors: Nuwan C. Hettige; Huashan Peng; Hanrong Wu; Xin Zhang; Volodymyr Yerko; Ying Zhang; Malvin Jefri; Vincent Soubannier; Gilles Maussion; Shaima Alsuwaidi; Anjie Ni; Cecilia Rocha; Jeyashree Krishnan; Vincent McCarty; Lilit Antonyan; Andreas Schuppert; Gustavo Turecki; Edward A. Fon; Thomas M. Durcan; Carl Ernst
• Keywords: Microcephaly; Forebrain

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 glioblastoma. To investigate the role of forebrain cell proliferation, we modeled syndrome using cells from three clinically diagnosed cases with two sex-matched healthy parents one unrelated control. Cells heterozygous loss showed significant reduction ratio G0/G1 stage cycle, frequency primary cilia. Engineered recapitulated this effect, while isogenic repair patient mutation reverted output markers to wild type. An engineered inducible line derived case demonstrated that dose-dependently affects all proliferation outputs measured. These findings provide strong support for critical importance levels controlling human brain growth health disease.