Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

Abstract
Article and author information
Metrics

Abstract

The balance between self-renewal and differentiation of neural progenitor cells (NPCs) dictates neurogenesis and proper brain development. We found that the RNA binding protein Sam68 is strongly expressed in neurogenic areas of the neocortex and supports the self-renewing potential of mouse NPCs. Knockout of Sam68 constricted the pool of proliferating NPCs by accelerating their cell cycle exit and differentiation into post-mitotic neurons. Sam68 function was linked to regulation of Aldh1a3 pre-mRNA 3'-end processing. Binding of Sam68 to an intronic polyadenylation site prevents its recognition and premature transcript termination, favouring expression of a functional enzyme. The lower ALDH1A3 expression and activity in Sam68^-/- NPCs results in reduced glycolysis and clonogenicity, thus depleting the embryonic NPC pool and limiting cortical expansion. Our study identifies Sam68 as a key regulator of NPC self-renewal and establishes a novel link between modulation of ALDH1A3 expression and maintenance of high glycolytic metabolism in the developing cortex.

Article and author information

Author details

Piergiorgio La Rosa

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

Competing interests
The authors declare that no competing interests exist.
Pamela Bielli

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

Competing interests
The authors declare that no competing interests exist.
Claudia Compagnucci

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

Competing interests
The authors declare that no competing interests exist.
Eleonora Cesari

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

Competing interests
The authors declare that no competing interests exist.
Elisabetta Volpe

Neuroimmunology, Fondazione Santa Lucia, Rome, Italy

Competing interests
The authors declare that no competing interests exist.
Stefano Farioli Vecchioli

Institute of Cell Biology and Neurobiology CNR, Rome, Italy

Competing interests
The authors declare that no competing interests exist.
Claudio Sette

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

For correspondence
claudio.sette@uniroma2.it

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2864-8266

Funding

Telethon (GGP14095)

Claudio Sette

Associazione Italiana Ricerca sul Cancro (IG14581)

Claudio Sette

Muscular Dystrophy Association

Claudio Sette

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Italian Ministry of Health. All of the animals were handled according to approved institutional animal care and use committee of the University ofRome Tor Vergata. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Rome Tor Vergata. Every effort was made to minimize suffering of mice.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.