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 (+5 others)
2018 Scientific Reports  
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
more » ... ers 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. Neural stem cells (NSCs) are a major focus of research owing to their capacity for self-renewal and their multipotency, both of which are determined by the expression of transcription factors and epigenetic regulations 1 . NSC biology is the result of a dynamic balance between the expansion and/or maintenance of an uncommitted stem cell pool and the processes of lineage restriction and differentiation 2,3 . Since the discovery of NSCs, researchers have been attempting to identify mechanisms underlying their maintenance, which might one day be exploited to repair tissue damage or improve the regenerative power of cells affected by neurodegenerative diseases (e.g., Parkinson's disease, Huntington's disease, multiple sclerosis) or spinal cord injury. A better understanding of the signalling cascades responsible for inducing proliferating NSCs to differentiate could therefore expand the potential uses of NSCs as therapeutic agents 4,5 . The Hedgehog (Hh) signalling pathway plays fundamental roles in the maintenance of stem cells, including the NSCs of the cerebellum 3,6 . By the late stages of embryogenesis, Hh glycoproteins are being secreted by differentiated Purkinje neurons in the cerebellum 7 . These proteins bind to and inactivate the transmembrane receptor Patched on nearby target cells, abrogating its repression of a second transmembrane receptor, Smoothened. The complex downstream signalling triggered by these events culminates in the expression of glioma-associated oncogene (Gli)-family transcription factors (Gli1, Gli2, and Gli3), whose targets comprise genes promoting both the proliferation and survival of NSCs in the embryonic and adult brains 8 . Our previous studies showed that Gli1 and Gli2 in cerebellar NSCs directly regulate the pluripotency transcription factor Nanog 3 . In subsequent studies, Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific RepoRts | (2018) 8:3523 |
doi:10.1038/s41598-018-21876-y pmid:29476172 pmcid:PMC5824884 fatcat:i56qakqohfdknas6lutjqngfru