Stem cells 2013 July-36

 

Regulation of neural stem cell differentiation by transcription factors HNF4-1 and MAZ-1.

Mol Neurobiol. 2013 Feb;47(1):228-40.

Wang Jiao, Cheng Hua, Li Xiao, Lu Wei, Wang Kai, Wen Tieqiao.

Laboratory of Molecular Neural Biology, Institute of Systems Biology, School of Life Sciences, Shanghai University, 99 Shang Da Road, Shanghai, 200444, China.

Abstract

Neural stem cells (NSCs) are promising candidates for a variety of neurological diseases due to their ability to differentiate into neurons, astrocytes, and oligodentrocytes. During this process, Rho GTPases are heavily involved in neuritogenesis, axon formation and dendritic development, due to their effects on the cytoskeleton through downstream effectors. The activities of Rho GTPases are controlled by Rho-GDP dissociation inhibitors (Rho-GDIs). As shown in our previous study, these are also involved in the differentiation of NSCs; however, little is known about the underlying regulatory mechanism. Here, we describe how the transcription factors hepatic nuclear factor (HNF4-1) and myc-associated zinc finger protein (MAZ-1) regulate the expression of Rho-GDIγ in the stimulation of NSC differentiation. Using a transfection of cis-element double-stranded oligodeoxynucleotides (ODNs) strategy, referred to as “decoy” ODNs, we examined the effects of HNF4-1 and MAZ-1 on NSC differentiation in the NSC line C17.2. Our results show that HNF4-1 and MAZ-1 decoy ODNs significantly knock down Rho-GDIγ gene transcription, leading to NSC differentiation towards neurons. We observed that HNF4-1 and MAZ-1 decoy ODNs are able enter to the cell nucleolus and specifically bind to their target transcription factors. Furthermore, the expression of Rho-GDIγ-mediated genes was identified, suggesting that the regulatory mechanism for the differentiation of NSCs is triggered by the transcription factors MAZ-1 and HNF4-1. These findings indicate that HNF4-1 and MAZ-1 regulate the expression of Rho-GDIγ and contribute to the differentiation of NSCs. Our findings provide a new perspective within regulatory mechanism research during differentiation of NSCs, especially the clinical application of transcription factor decoys in vivo, suggesting potential therapeutic strategies for neurodegenerative disease.

 

Press release

Direct neuronal differentiation by regulation of “decoy strategy”

Research published in Molecular Neurobiology reported that transfection factors regulate the expression of Rho-GDIγ and contribute to the differentiation of neural stem cells (NSCs), suggesting potential therapeutic prospects for neurodegenerative disease.

NSCs can differentiated into neurons, astrocytes and oligodendrocytes, which make sense in neural injury and repair. It is particularly important to regulate neuronal differentiation from NSCs both in basic research and clinical research. However, to date it has been difficult to achieve direct neuronal differentiation of NSCs.

Researchers from the Shanghai University investigated the effects of transfection factors HNF4-1 and MAZ-1 on NSC differentiation by using a transfection of cis-element double-stranded oligodeoxynucleotides strategy. Results showed that neuronal differentiation was mediated by inhibiting Rho-GDIγ signaling and activating Rho Proteins Cdc42,RhoA and Rac1. These results for the first time identified the important role of HNF4-1 and MAZ-1 in regulating neuronal differentiation from NSCs, suggesting a guiding role in study of cell differentiation. It is also significant for drug design in targeting regulation.

Dr. Tieqiao Wen who led this study said, “Although a lot of research has demonstrated that the proliferation and differentiation of NSCs were affected by internal and external, the precise regulatory mechanisms involved in the control of NSC differentiation are still unclear. The clinical use of regulation of NSC differentiation has a long way to go. This study by “decoy strategy” provides a method at molecular level for neuronal differentiation. It may be a step towards preclinical application”.

 

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