LSD1/KDM1A is essential for neural stem cell differentiation in mice

• Type of Material: Article
• Authors: Carrie Falkenberry, Emory University; Monica Reeves, Emory University; A. Scott, No affiliation; D.A. Myrick, No affiliation; C. Fallini, University of Rhode Island, Kingston; Gary Bassell, Emory University; David J Katz, Emory University
• Language: English
• Date: 2023-12-03
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101/2023.12.02.569711
• Title of Journal or Parent Work: bioRxiv
• Start Page: 569711
• Grant/Funding Information: This work was funded by grants to D.J.K. (NSF IOS1931697, Emory University Research Council, pilot funding from P01GM085354 (Dalton, PI) and NINDS 1R56NS122964-01A1). A.S. was supported by NIH F31 5F31HD098816. M.R. and A.S. were supported by the Emory GMB training grants (T32GM008490-21 and T32GM149422-01). This study was supported in part by the Mouse Transgenic and Gene Targeting Core (TMF), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the National Center for Advancing Translational Science of the National Institutes of Health (UL1TR000454).
• Keywords: neural stem cell; LSD1; central nervous system; neural stem cell differentiation
• Research Categories: Biology, Molecular; Biology, Neuroscience

Abstract

The proper regulation of neural stem cell differentiation is required for the proper specification of the central nervous system. Here we investigated the function of the H3K4me1/2 demethylase LSD1/KDM1A during neural stem differentiation in mice. Conditional deletion of LSD1 in nestin- positive neural stem cells results in 100% perinatal lethality after birth with severe motor coordination deficits, retarded growth and defects in brain morphology. Despite these severe defects, motor neuron progenitors and the initial motor neuron population are specified normally and motor neurons with normal morphology can be cultured from these mice in vitro. However, motor neurons cultured from mice lacking LSD1 in neural stem cells continue to inappropriately maintain critical neural stem cell proteins. Taken together these results suggest that, as in other mouse stem cell populations, LSD1 is required to deactivate the stem cell program to enable normal neural stem cell differentiation. However, unlike in other mouse stem cell populations, the inappropriate maintenance of the stem cell program during neural stem cell differentiation may compromise neuronal function rather than neuronal specification.