Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain

• Published in: Development (Cambridge) Vol. 137; no. 11; pp. 1875 - 1885
• Main Authors: Shimizu, Takeshi, Nakazawa, Masato, Kani, Shuichi, Bae, Young-Ki, Shimizu, Takashi, Kageyama, Ryoichiro, Hibi, Masahiko
• Format: Journal Article
• Language: English
• Published: England 01.06.2010
• Subjects: Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - deficiency; Basic Helix-Loop-Helix Transcription Factors - genetics; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Line; DNA Primers - genetics; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Female; Gene Expression Regulation, Developmental; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Neurogenesis - genetics; Neurogenesis - physiology; Neurons - cytology; Neurons - metabolism; Pregnancy; Promoter Regions, Genetic; Prosencephalon - embryology; Prosencephalon - metabolism; Recombinant Proteins - genetics; Repressor Proteins - deficiency; Repressor Proteins - genetics; Telencephalon - embryology; Telencephalon - metabolism; Zinc Fingers - genetics
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.047167

Precise control of neuronal differentiation is necessary for generation of a variety of neurons in the forebrain. However, little is known about transcriptional cascades, which initiate forebrain neurogenesis. Here we show that zinc finger genes Fezf1 and Fezf2, which encode transcriptional repressors, are expressed in the early neural stem (progenitor) cells and control neurogenesis in mouse dorsal telencephalon. Fezf1- and Fezf2-deficient forebrains display upregulation of Hes5 and downregulation of neurogenin 2, which is known to be negatively regulated by Hes5. We show that FEZF1 and FEZF2 bind to and directly repress the promoter activity of Hes5. In Fezf1- and Fezf2-deficient telencephalon, the differentiation of neural stem cells into early-born cortical neurons and intermediate progenitors is impaired. Loss of Hes5 suppresses neurogenesis defects in Fezf1- and Fezf2-deficient telencephalon. Our findings reveal that Fezf1 and Fezf2 control differentiation of neural stem cells by repressing Hes5 and, in turn, by derepressing neurogenin 2 in the forebrain.