Foxm1 controls a pro-stemness microRNA network in neural stem cells

Zein Mersini Besharat; Luana Abballe; Francesco Cicconardi; Arjun Bhutkar; Luigi Grassi; Loredana Le Pera; Marta Moretti; Mauro Chinappi; Daniel D'Andrea; Angela Mastronuzzi; Alessandra Ianari; Alessandra Vacca; Enrico De Smaele; Franco Locatelli; Agnese Po; Evelina Miele; Elisabetta Ferretti

doi:10.1038/s41598-018-21876-y

Foxm1 controls a pro-stemness microRNA network in neural stem cells

Sci Rep. 2018 Feb 23;8(1):3523. doi: 10.1038/s41598-018-21876-y.

Authors

Zein Mersini Besharat¹, Luana Abballe¹, Francesco Cicconardi², Arjun Bhutkar³, Luigi Grassi^{4

5}, Loredana Le Pera⁶, Marta Moretti⁷, Mauro Chinappi⁸, Daniel D'Andrea⁹, Angela Mastronuzzi¹⁰, Alessandra Ianari³, Alessandra Vacca¹, Enrico De Smaele¹, Franco Locatelli¹⁰, Agnese Po¹¹, Evelina Miele^{6

10}, Elisabetta Ferretti^{12

13}

Affiliations

¹ Department of Experimental Medicine, Sapienza University, Rome, 00161, Italy.
² Institute of Ecology, University of Innsbruck, Technikerstrasse 25, Innsbruck, a-6020, Austria.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, United States.
⁴ Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
⁵ National Health Service Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
⁶ Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, 00161, Italy.
⁷ Department of Molecular Medicine, Sapienza University, Rome, 00161, Italy.
⁸ Department of Industrial Engineering, University of Rome Tor Vergata, Via del Politecnico 1, Rome, 00133, Italy.
⁹ Centre for Cell Signalling and Inflammation, Imperial College, London, SW72AZ, UK.
¹⁰ Department of Pediatric Hematology-Oncology and Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, 00165, Italy.
¹¹ Department of Molecular Medicine, Sapienza University, Rome, 00161, Italy. agnese.po@uniroma1.it.
¹² Department of Experimental Medicine, Sapienza University, Rome, 00161, Italy. elisabetta.ferretti@uniroma1.it.
¹³ Neuromed Institute, Pozzilli, 86077, Italy. elisabetta.ferretti@uniroma1.it.

Abstract

Cerebellar neural stem cells (NSCs) require Hedgehog-Gli (Hh-Gli) signalling for their maintenance and Nanog expression for their self-renewal. To identify novel molecular features of this regulatory pathway, we used next-generation sequencing technology to profile mRNA and microRNA expression in cerebellar NSCs, before and after induced differentiation (Diff-NSCs). Genes with higher transcript levels in NSCs (vs. Diff-NSCs) included Foxm1, which proved to be directly regulated by Gli and Nanog. Foxm1 in turn regulated several microRNAs that were overexpressed in NSCs: miR-130b, miR-301a, and members of the miR-15~16 and miR-17~92 clusters and whose knockdown significantly impaired the neurosphere formation ability. Our results reveal a novel Hh-Gli-Nanog-driven Foxm1-microRNA network that controls the self-renewal capacity of NSCs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Cell Differentiation
Cell Proliferation
Cerebellum / cytology
Cerebellum / growth & development
Cerebellum / metabolism*
Forkhead Box Protein M1 / genetics*
Forkhead Box Protein M1 / metabolism
Gene Expression Regulation, Developmental*
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism
High-Throughput Nucleotide Sequencing
Mice
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism
Nanog Homeobox Protein / genetics*
Nanog Homeobox Protein / metabolism
Neural Stem Cells / cytology
Neural Stem Cells / metabolism*
Neurogenesis / genetics*
Primary Cell Culture
Signal Transduction
Spheroids, Cellular / cytology
Spheroids, Cellular / metabolism
Zinc Finger Protein GLI1 / genetics*
Zinc Finger Protein GLI1 / metabolism

Substances

Forkhead Box Protein M1
Foxm1 protein, mouse
Gli1 protein, mouse
Hedgehog Proteins
MIRN130 microRNA, mouse
MIRN17-92 microRNA, mouse
MIRN301 microRNA, mouse
MicroRNAs
Mirn15a microRNA, mouse
Nanog Homeobox Protein
Nanog protein, mouse
Shh protein, mouse
Zinc Finger Protein GLI1