1. PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.
- Author
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Rasool, Dilan, Burban, Audrey, Sharanek, Ahmad, Madrigal, Ariel, Hu, Jinghua, Yan, Keqin, Qu, Dianbo, Voss, Anne K, Slack, Ruth S, Thomas, Tim, Bonni, Azad, Picketts, David J, Soleimani, Vahab D, Najafabadi, Hamed S, and Jahani-Asl, Arezu
- Abstract
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS. Synopsis: This study reveals genome wide binding of PHF6 in the developing cortex and shows that it alters neural stem cells via regulation of Ephrin receptors. PHF6/EphR pathway is impaired in the rare X-linked intellectual disability, BFLS. PHF6 regulates neural stem cell (NSC) fate in the developing brain. PHF6 binds gene regulatory elements of Ephrin receptors (EphR) to upregulate their expression and alter neurogenesis. BFLS mice exhibit altered NSC and progenitor populations, and deregulation of Ephrin receptors. EphR-A family of receptors rescues PHF6 loss-of-function defects in BFLS mice-derived eNSCs. This study reveals genome wide binding of PHF6 in the developing cortex and shows that it alters neural stem cells via regulation of Ephrin receptors. PHF6/EphR pathway is impaired in the rare X-linked intellectual disability, BFLS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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